rs779027774

Variant names:

• chr5-218369-G-A
• rs779027774
• NM_004168.4:c.14G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-218369-G-A
• chr5-218369-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004168.4(SDHA):​c.14G>A​(p.Arg5Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,304,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.275
• Publications: 2 publications found

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:):

CCDC127 (HGNC:30520): (coiled-coil domain containing 127) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06117317).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004168.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	NM_004168.4	MANE Select	c.14G>A	p.Arg5Gln	missense	Exon 1 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.14G>A	p.Arg5Gln	missense	Exon 1 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.14G>A	p.Arg5Gln	missense	Exon 1 of 13	NP_001317687.1	D6RFM5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.14G>A	p.Arg5Gln	missense	Exon 1 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.14G>A		non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.14G>A	p.Arg5Gln	missense	Exon 1 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000269 AC: 3 AN: 111436 AF XY: 0.0000465

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1304102 Hom.: 0 Cov.: 31 AF XY: 0.00000311 AC XY: 2 AN XY: 643922

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26820

American (AMR) AF: 0.00 AC: 0 AN: 24960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20262

East Asian (EAS) AF: 0.00 AC: 0 AN: 30998

South Asian (SAS) AF: 0.00 AC: 0 AN: 65328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3664

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1044962

Other (OTH) AF: 0.00 AC: 0 AN: 53376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000178 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.8
DANN	Benign	0.91
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.28
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.076
Sift	Benign	0.23	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.31		Loss of methylation at R5 (P = 0.0024)
MVP		0.35
MPC		1.1
ClinPred		0.082	T
GERP RS		1.8
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.50
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs779027774; hg19: chr5-218484;