rs781764920

Variant names:

• chr5-224432-C-G
• NM_004168.4:c.223C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-224432-C-G
• chr5-224432-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004168.4(SDHA):​c.223C>G​(p.Arg75Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.223C>G	p.Arg75Gly	missense_variant	Exon 3 of 15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.223C>G	p.Arg75Gly	missense_variant	Exon 3 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.223C>G		non_coding_transcript_exon_variant	Exon 3 of 24			ENSP00000499215.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R75G variant (also known as c.223C>G), located in coding exon 3 of the SDHA gene, results from a C to G substitution at nucleotide position 223. The arginine at codon 75 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.1	.;M;.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.2	.;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.89
MutPred		0.75		Loss of methylation at R75 (P = 0.0015);Loss of methylation at R75 (P = 0.0015);Loss of methylation at R75 (P = 0.0015);Loss of methylation at R75 (P = 0.0015);
MVP		0.91
MPC		1.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-224547;