chr9-133352518-A-T

Variant names:

• chr9-133352518-A-T
• rs398122806
• NM_003172.4:c.679T>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1 PM2 PP2 PP3_Strong

The NM_003172.4(SURF1):​c.679T>A​(p.Trp227Arg) 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 Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SURF1 NM_003172.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.89
• Publications: 0 publications found

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]

SURF1 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• mitochondrial complex IV deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Charcot-Marie-Tooth disease type 4K

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with cardiomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_003172.4 (SURF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: -0.68006 (below the threshold of 3.09). Trascript score misZ: -1.3185 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome with leukodystrophy, Leigh syndrome, mitochondrial complex IV deficiency, nuclear type 1, Charcot-Marie-Tooth disease type 4K, Leigh syndrome with cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SURF1	NM_003172.4	c.679T>A	p.Trp227Arg	missense_variant	Exon 7 of 9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.352T>A	p.Trp118Arg	missense_variant	Exon 6 of 8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8	c.679T>A	p.Trp227Arg	missense_variant	Exon 7 of 9	1	NM_003172.4	ENSP00000361042.3
SURF1	ENST00000615505.4	c.352T>A	p.Trp118Arg	missense_variant	Exon 6 of 8	1		ENSP00000482067.1
SURF1	ENST00000437995.1	n.589T>A		non_coding_transcript_exon_variant	Exon 6 of 8	5
SURF1	ENST00000495952.5	n.669T>A		non_coding_transcript_exon_variant	Exon 3 of 5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Uncertain:1

Sep 20, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan with arginine at codon 227 of the SURF1 protein (p.Trp227Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). 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. Studies have shown that this missense change alters SURF1 gene expression (PMID: 29933018). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with mitochondrial complex IV deficiency (PMID: 21937992). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.
PhyloP100		8.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-12	D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.91		Gain of disorder (P = 0.0018);.;
MVP		0.99
MPC		0.24
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.98
Mutation Taster		=11/89	disease causing

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: rs398122806; hg19: chr9-136219373;