rs34504623

Variant names:

• chr5-254521-C-T
• rs34504623
• NM_004168.4:c.1908+15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004168.4(SDHA):​c.1908+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,540,732 control chromosomes in the GnomAD database, including 9,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (680 hom., cov: 28)
  • Exomes 𝑓: 0.11 (9236 hom.)
• Consequence: SDHA NM_004168.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.98
• Publications: 1 publications found

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]

SDHA Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• neurodegeneration with ataxia and late-onset optic atrophy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1GG

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286001 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 5-254521-C-T is Benign according to our data. Variant chr5-254521-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1908+15C>T		intron_variant	Intron 14 of 14	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.1908+15C>T		intron_variant	Intron 14 of 14	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.*641+15C>T		intron_variant	Intron 13 of 23			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.0791 AC: 11899 AN: 150508 Hom.: 680 Cov.: 28

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0706

Gnomad AMR AF: 0.0692

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.00156

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0822

GnomAD2 exomes AF: 0.0783 AC: 12239 AN: 156268 AF XY: 0.0766

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0601

Gnomad ASJ exome AF: 0.0962

Gnomad EAS exome AF: 0.000176

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0977

GnomAD4 exome AF: 0.108 AC: 150186 AN: 1390108 Hom.: 9236 Cov.: 31 AF XY: 0.105 AC XY: 72411 AN XY: 686536

African (AFR) AF: 0.0176 AC: 539 AN: 30578

American (AMR) AF: 0.0643 AC: 2310 AN: 35940

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2483 AN: 24806

East Asian (EAS) AF: 0.000139 AC: 5 AN: 36090

South Asian (SAS) AF: 0.0167 AC: 1326 AN: 79202

European-Finnish (FIN) AF: 0.127 AC: 6206 AN: 48882

Middle Eastern (MID) AF: 0.0344 AC: 138 AN: 4014

European-Non Finnish (NFE) AF: 0.122 AC: 131466 AN: 1073430

Other (OTH) AF: 0.0999 AC: 5713 AN: 57166

GnomAD4 genome AF: 0.0790 AC: 11895 AN: 150624 Hom.: 680 Cov.: 28 AF XY: 0.0762 AC XY: 5605 AN XY: 73572

African (AFR) AF: 0.0213 AC: 861 AN: 40414

American (AMR) AF: 0.0691 AC: 1050 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 357 AN: 3466

East Asian (EAS) AF: 0.00157 AC: 8 AN: 5102

South Asian (SAS) AF: 0.0157 AC: 75 AN: 4772

European-Finnish (FIN) AF: 0.114 AC: 1205 AN: 10542

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.119 AC: 8095 AN: 67842

Other (OTH) AF: 0.0813 AC: 170 AN: 2090

Alfa AF: 0.0938 Hom.: 125

Bravo AF: 0.0746

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Oct 31, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mitochondrial complex II deficiency, nuclear type 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Leigh syndrome Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Pheochromocytoma/paraganglioma syndrome 5 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

May 14, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary pheochromocytoma-paraganglioma Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.086
DANN	Benign	0.34
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34504623; hg19: chr5-254636; COSMIC: COSV53767694; COSMIC: COSV53767694;