5-233550-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_004168.4(SDHA):c.969C>T(p.Gly323=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 1,614,066 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G323G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (83 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: -1.74

Genes affected

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 5-233550-C-T is Benign according to our data. Variant chr5-233550-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141242.We mark this variant Likely_benign, oryginal submissions are: {Benign=12, Likely_benign=1, Uncertain_significance=1}. Variant chr5-233550-C-T is described in Lovd as [Benign]. Variant chr5-233550-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.74 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00453 (690/152224) while in subpopulation SAS AF= 0.0193 (93/4814). AF 95% confidence interval is 0.0161. There are 4 homozygotes in gnomad4. There are 328 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHA	NM_004168.4	c.969C>T	p.Gly323=	synonymous_variant	8/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11	c.969C>T	p.Gly323=	synonymous_variant	8/15	1	NM_004168.4	P1

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 694 AN: 152106 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00579

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00724 AC: 1821 AN: 251496 Hom.: 23 AF XY: 0.00850 AC XY: 1156 AN XY: 135922

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0231

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00607

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00707 AC: 10329 AN: 1461842 Hom.: 83 Cov.: 32 AF XY: 0.00760 AC XY: 5524 AN XY: 727216

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.0246

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0220

Gnomad4 FIN exome AF: 0.00168

Gnomad4 NFE exome AF: 0.00635

Gnomad4 OTH exome AF: 0.00690

GnomAD4 genome AF: 0.00453 AC: 690 AN: 152224 Hom.: 4 Cov.: 33 AF XY: 0.00441 AC XY: 328 AN XY: 74422

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.0262

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0193

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00579

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00545 Hom.: 1

Bravo AF: 0.00435

EpiCase AF: 0.00774

EpiControl AF: 0.00717

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 30, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SDHA p.Gly275Gly variant was not identified in the literature nor was it identified in the Cosmic, MutDB or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs142849100) as "With Likely benign allele". The variant was identified in ClinVar, classified as benign and likely benign. There are 7 submissions for this variant in ClinVar: 3 submissions of benign (Ambry Genetics, Invitae, and Prevention Genetics) and 4 submissions of likely benign (3 from Illumina and 1 from GeneDx). The variant was also identified in Clinvitae with one submission from Invitae of likely benign. The variant was identified in control databases in 1956 of 282892 chromosomes (23 homozygous) at a frequency of 0.006914 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 246 of 10370 chromosomes (freq: 0.02372), South Asian in 706 of 30616 chromosomes (freq: 0.02306), Other in 68 of 7228 chromosomes (freq: 0.009408), European (non-Finnish) in 782 of 129192 chromosomes (freq: 0.006053), Latino in 82 of 35440 chromosomes (freq: 0.002314), European (Finnish) in 44 of 25122 chromosomes (freq: 0.001751), African in 27 of 24970 chromosomes (freq: 0.001081) and East Asian in 1 of 19954 chromosomes (freq: 0.00005). The p.(Gly275Gly) variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site, however 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. Computational evidence is only available from MutationTaster, and the variant is predicted to be disease causing. The Gly275 residue is conserved across mammals and other organisms. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SDHA: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 27, 2020	- -

Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Leigh syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Paragangliomas 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary pheochromocytoma-paraganglioma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	8.3
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142849100; hg19: chr5-233665; COSMIC: COSV53772676; COSMIC: COSV53772676;