rs745884899

Positions:

• chr5-228241-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004168.4(SDHA):​c.678G>A​(p.Met226Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.50

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4	c.678G>A	p.Met226Ile	missense_variant	6/15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.678G>A	p.Met226Ile	missense_variant	6/15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.678G>A		non_coding_transcript_exon_variant	6/24			ENSP00000499215.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251170 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461604 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 226 of the SDHA protein (p.Met226Ile). This variant is present in population databases (rs745884899, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 567060). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SDHA protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.060	T;T;T
Polyphen		0.089	B;P;.
Vest4		0.80
MutPred		0.51		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;
MVP		0.81
MPC		0.71
ClinPred		0.91	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
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: rs745884899; hg19: chr5-228356;