5-218349-A-C

Position:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_004168.4(SDHA):​c.-7A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,455,416 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

SDHA
NM_004168.4 5_prime_UTR

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:11

Conservation

PhyloP100: 0.187
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 5-218349-A-C is Benign according to our data. Variant chr5-218349-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 371942.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=5, Benign=1}. Variant chr5-218349-A-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000782 (119/152270) while in subpopulation NFE AF= 0.00118 (80/67998). AF 95% confidence interval is 0.000968. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SDHANM_004168.4 linkuse as main transcriptc.-7A>C 5_prime_UTR_variant 1/15 ENST00000264932.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SDHAENST00000264932.11 linkuse as main transcriptc.-7A>C 5_prime_UTR_variant 1/151 NM_004168.4 P1P31040-1

Frequencies

GnomAD3 genomes
AF:
0.000789
AC:
120
AN:
152162
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000785
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.00118
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000666
AC:
72
AN:
108066
Hom.:
0
AF XY:
0.000800
AC XY:
50
AN XY:
62516
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000280
Gnomad ASJ exome
AF:
0.00185
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000885
Gnomad FIN exome
AF:
0.000169
Gnomad NFE exome
AF:
0.000793
Gnomad OTH exome
AF:
0.00181
GnomAD4 exome
AF:
0.00103
AC:
1341
AN:
1303146
Hom.:
1
Cov.:
31
AF XY:
0.00105
AC XY:
673
AN XY:
642938
show subpopulations
Gnomad4 AFR exome
AF:
0.0000374
Gnomad4 AMR exome
AF:
0.000460
Gnomad4 ASJ exome
AF:
0.00382
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00102
Gnomad4 FIN exome
AF:
0.0000594
Gnomad4 NFE exome
AF:
0.00105
Gnomad4 OTH exome
AF:
0.00129
GnomAD4 genome
AF:
0.000782
AC:
119
AN:
152270
Hom.:
0
Cov.:
34
AF XY:
0.000672
AC XY:
50
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000784
Gnomad4 ASJ
AF:
0.00288
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.00118
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.0000530
Hom.:
0
Bravo
AF:
0.000824
Asia WGS
AF:
0.000290
AC:
1
AN:
3466

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:11
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:5
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 20, 2017- -
Likely benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoNov 01, 2022- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024SDHA: BS1 -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 01, 2017This 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. -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 07, 2021- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 03, 2015The c.-7A>C alteration is located in the 5' untranslated region (5'UTR) of the SDHA gene. This alteration consists of a A to C substitution nucleotides upstream from the first translated codon. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submittercurationSema4, Sema4Oct 02, 2020- -
Paragangliomas 5 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylAug 31, 2016- -
Likely benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 21, 2023This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Leigh syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 03, 2023- -
Hereditary pheochromocytoma-paraganglioma Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
8.2
DANN
Benign
0.32
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs751633537; hg19: chr5-218464; API