rs151266052

chr5-240448-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_004168.4(SDHA):c.1523C>T(p.Thr508Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000487 in 1,609,846 control chromosomes in the GnomAD database, including 8 homozygotes. 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. T508S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (8 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:7
• Conservation: PhyloP100: 7.44

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 -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_004168.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.05164352).
• BP6: Variant 5-240448-C-T is Benign according to our data. Variant chr5-240448-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39585.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=4, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00229 (349/152318) while in subpopulation AFR AF= 0.00743 (309/41568). AF 95% confidence interval is 0.00675. There are 0 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHA	NM_004168.4	c.1523C>T	p.Thr508Ile	missense_variant	11/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11	c.1523C>T	p.Thr508Ile	missense_variant	11/15	1	NM_004168.4	P1

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000599 AC: 150 AN: 250468 Hom.: 1 AF XY: 0.000457 AC XY: 62 AN XY: 135610

Gnomad AFR exome AF: 0.00738

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000298 AC: 435 AN: 1457528 Hom.: 8 Cov.: 29 AF XY: 0.000251 AC XY: 182 AN XY: 725220

Gnomad4 AFR exome AF: 0.00996

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000981

GnomAD4 genome AF: 0.00229 AC: 349 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74476

Gnomad4 AFR AF: 0.00743

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000723 Hom.: 1

Bravo AF: 0.00241

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000758 AC: 92

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 23, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2020	This variant is associated with the following publications: (PMID: 22972948, 26642834, 23174333, 28724664, 29778030) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SDHA: PP3, BS1 -

Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2012	- -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 07, 2018	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 19, 2018	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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.052	T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
Sift4G	Uncertain	0.046	D;T;D;T
Polyphen		0.38, 0.21	.;B;B;.
Vest4		0.97
MVP		0.87
MPC		0.79
ClinPred		0.031	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.70

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: rs151266052; hg19: chr5-240563;