rs76896145

chr5-236534-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP4_Strong BP6

The NM_004168.4(SDHA):c.1367C>T(p.Ser456Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S456W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 7.58

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 Likely_benign. Variant got -4 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.021521896).
• BP6: Variant 5-236534-C-T is Benign according to our data. Variant chr5-236534-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539695.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}. Variant chr5-236534-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHA	NM_004168.4	c.1367C>T	p.Ser456Leu	missense_variant	10/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11	c.1367C>T	p.Ser456Leu	missense_variant	10/15	1	NM_004168.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152064 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000343 AC: 478 AN: 1392702 Hom.: 0 Cov.: 32 AF XY: 0.000355 AC XY: 246 AN XY: 692060

Gnomad4 AFR exome AF: 0.000184

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.0000393

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000515

Gnomad4 FIN exome AF: 0.000458

Gnomad4 NFE exome AF: 0.000359

Gnomad4 OTH exome AF: 0.000259

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74402

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00377 Hom.: 0

ExAC AF: 0.0236 AC: 2859

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SDHA p.Ser408Leu variant was not identified in the literature or in the Cosmic database but was identified in dbSNP (ID: rs76896145), ClinVar (reported as benign by Invitae for mitochondrial complex II deficiency and paragangliomas 5) and LOVD 3.0. The variant was identified in control databases in 21 of 273542 chromosomes at a frequency of 0.000077 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24354 chromosomes (freq: 0.000164), European (non-Finnish) in 16 of 123988 chromosomes (freq: 0.000129) and South Asian in 1 of 28962 chromosomes (freq: 0.000035); it was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), and Other populations. The p.Ser408 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, and MutationTaster) suggest that the variant may impact the protein; 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. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.022	T;T;T;T
MetaSVM	Benign	-0.43	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.64
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.93
gMVP		0.96

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: rs76896145; hg19: chr5-236649; COSMIC: COSV53768124; COSMIC: COSV53768124;