chr5-251471-G-C

Variant names:

• chr5-251471-G-C
• rs375883981
• NM_004168.4:c.1794+3G>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_004168.4(SDHA):​c.1794+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SDHA NM_004168.4 splice_region, intron
• Scores: Splicing: ADA: 0.02456
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 0.632

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]

ENSG00000286001 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-251471-G-C is Benign according to our data. Variant chr5-251471-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229686.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1794+3G>C		splice_region_variant, intron_variant	Intron 13 of 14	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.1794+3G>C		splice_region_variant, intron_variant	Intron 13 of 14	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.*527+3G>C		splice_region_variant, intron_variant	Intron 12 of 23			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250688 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461594 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Feb 08, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.00025 (9/35396 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper SDHA mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. -

May 12, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

SDHA-related disorder Uncertain:1

Aug 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SDHA c.1794+3G>C variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.025% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar ranging from likely benign to uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/229686/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Oct 06, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.4
DANN	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.025
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.12		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: rs375883981; hg19: chr5-251586;