rs28933402

Variant names:

• chr9-133353893-C-T
• rs28933402
• NM_003172.4:c.371G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_003172.4(SURF1):​c.371G>A​(p.Gly124Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SURF1 NM_003172.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.52

Genes affected

SURF1 (HGNC:11474): (SURF1 cytochrome c oxidase assembly factor) This gene encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex. The protein is a member of the SURF1 family, which includes the related yeast protein SHY1 and rickettsial protein RP733. The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Surfeit locus protein 1 (size 299) in uniprot entity SURF1_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in NM_003172.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 9-133353893-C-T is Pathogenic according to our data. Variant chr9-133353893-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12768.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-133353893-C-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SURF1	NM_003172.4	c.371G>A	p.Gly124Glu	missense_variant	Exon 5 of 9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.44G>A	p.Gly15Glu	missense_variant	Exon 4 of 8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8	c.371G>A	p.Gly124Glu	missense_variant	Exon 5 of 9	1	NM_003172.4	ENSP00000361042.3
SURF1	ENST00000615505.4	c.44G>A	p.Gly15Glu	missense_variant	Exon 4 of 8	1		ENSP00000482067.1
SURF1	ENST00000437995.1	n.317G>A		non_coding_transcript_exon_variant	Exon 4 of 8	5
SURF1	ENST00000495952.5	n.361G>A		non_coding_transcript_exon_variant	Exon 1 of 5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Pathogenic:1

Jun 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with glutamic acid at codon 124 of the SURF1 protein (p.Gly124Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with SURF1-related conditions (PMID: 10746561). It has also been observed to segregate with disease in related individuals. This variant is also known as G385A. ClinVar contains an entry for this variant (Variation ID: 12768). Experimental studies have shown that this variant affects SURF1 protein function (PMID: 20624914). For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Feb 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.6	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.98		Gain of disorder (P = 0.0293);.;
MVP		0.99
MPC		0.22
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28933402; hg19: chr9-136220748;