5-228247-T-G

Position:

• chr5-228247-T-G

Variant summary

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

The NM_004168.4(SDHA):​c.684T>G​(p.Asn228Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N228S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.866

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 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	UniProt
SDHA	NM_004168.4	c.684T>G	p.Asn228Lys	missense_variant	6/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11	c.684T>G	p.Asn228Lys	missense_variant	6/15	1	NM_004168.4	P1

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	0.19
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.0090
DANN	Benign	0.76
DEOGEN2	Benign	0.26	T;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L;.;.
MutationTaster	Benign	0.0093	P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.093	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.49
MutPred		0.54		Gain of ubiquitination at N228 (P = 0.0198);Gain of ubiquitination at N228 (P = 0.0198);.;
MVP		0.081
MPC		0.57
ClinPred		0.079	T
GERP RS		-5.3
Varity_R		0.25
gMVP		0.59

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: rs2115272; hg19: chr5-228362;