5-218395-C-T

Variant names:

• chr5-218395-C-T
• rs1192077362
• NM_004168.4:c.40C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004168.4(SDHA):​c.40C>T​(p.Arg14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 1,294,294 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 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. R14P) has been classified as Uncertain significance.

• 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:4
• Conservation: PhyloP100: 0.333
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.40C>T	p.Arg14Trp	missense	Exon 1 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.40C>T	p.Arg14Trp	missense	Exon 1 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.40C>T	p.Arg14Trp	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.40C>T	p.Arg14Trp	missense	Exon 1 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.40C>T		non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.40C>T	p.Arg14Trp	missense	Exon 1 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000155 AC: 2 AN: 1294294 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 638762

⚠️ 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: 26524

American (AMR) AF: 0.00 AC: 0 AN: 23256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19812

East Asian (EAS) AF: 0.00 AC: 0 AN: 30796

South Asian (SAS) AF: 0.00 AC: 0 AN: 63306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3630

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1040934

Other (OTH) AF: 0.00 AC: 0 AN: 52958

⚠️ 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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	-	not provided (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	Uncertain	0.41
BayesDel_addAF	Benign	0.0030	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.33
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.57		Loss of methylation at R14 (P = 0.0294)
MVP		0.65
MPC		1.3
ClinPred		0.53	D
GERP RS		2.8
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.14
gMVP		0.60
Mutation Taster		=92/8	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: rs1192077362; hg19: chr5-218510;