5-218368-C-G

Variant names:

• chr5-218368-C-G
• rs770866830
• NM_004168.4:c.13C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_004168.4(SDHA):​c.13C>G​(p.Arg5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000307 in 1,304,980 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.166
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059296817).
• BP6: Variant 5-218368-C-G is Benign according to our data. Variant chr5-218368-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 966890.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.13C>G	p.Arg5Gly	missense_variant	Exon 1 of 15	ENST00000264932.11	NP_004159.2
CCDC127	NM_145265.3	c.-286G>C		upstream_gene_variant		ENST00000296824.4	NP_660308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.13C>G	p.Arg5Gly	missense_variant	Exon 1 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.13C>G		non_coding_transcript_exon_variant	Exon 1 of 24			ENSP00000499215.1
CCDC127	ENST00000296824.4	c.-286G>C		upstream_gene_variant		1	NM_145265.3	ENSP00000296824.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000179 AC: 2 AN: 111544 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000307 AC: 4 AN: 1304980 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 644360

African (AFR) AF: 0.00 AC: 0 AN: 26834

American (AMR) AF: 0.0000798 AC: 2 AN: 25052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20278

East Asian (EAS) AF: 0.00 AC: 0 AN: 31010

South Asian (SAS) AF: 0.00 AC: 0 AN: 65434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3672

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1045522

Other (OTH) AF: 0.00 AC: 0 AN: 53378

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000178 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1

Jan 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 5 of the SDHA protein (p.Arg5Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 966890). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SDHA protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Benign:1

May 23, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.64
DEOGEN2	Benign	0.26	T;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.059	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N;.;N
PhyloP100		-0.17
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.51	.;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.26	.;T;T;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.0020	.;B;B;.
Vest4		0.13
MutPred		0.34		Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);
MVP		0.38
MPC		1.3
ClinPred		0.069	T
GERP RS		0.23
PromoterAI		-0.061	Neutral
Varity_R		0.079
gMVP		0.58
Mutation Taster		=96/4	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: rs770866830; hg19: chr5-218483;