5-225548-G-C

Position:

• chr5-225548-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004168.4(SDHA):​c.442G>C​(p.Ala148Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.04

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4	c.442G>C	p.Ala148Pro	missense_variant	4/15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.442G>C	p.Ala148Pro	missense_variant	4/15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.442G>C		non_coding_transcript_exon_variant	4/24			ENSP00000499215.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.052
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.75	N;N
REVEL	Benign	0.23
Sift	Benign	0.20	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.0030	B;P
Vest4		0.67
MutPred		0.42		Gain of catalytic residue at P147 (P = 0.0168);Gain of catalytic residue at P147 (P = 0.0168);
MVP		0.78
MPC		0.63
ClinPred		0.71	D
GERP RS		5.4
Varity_R		0.67
gMVP		0.92

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: chr5-225663;