chr9-133351945-TA-T

Position:

• chr9-133351945-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_003172.4(SURF1):​c.870del​(p.Phe290LeufsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SURF1 NM_003172.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.396

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0365 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-133351945-TA-T is Pathogenic according to our data. Variant chr9-133351945-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2726031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SURF1	NM_003172.4	c.870del	p.Phe290LeufsTer55	frameshift_variant	9/9	ENST00000371974.8
SURF1	NM_001280787.1	c.543del	p.Phe181LeufsTer?	frameshift_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SURF1	ENST00000371974.8	c.870del	p.Phe290LeufsTer55	frameshift_variant	9/9	1	NM_003172.4	P1
SURF1	ENST00000615505.4	c.543del	p.Phe181LeufsTer?	frameshift_variant	8/8	1
SURF1	ENST00000437995.1	n.780del		non_coding_transcript_exon_variant	8/8	5
SURF1	ENST00000495952.5	n.860del		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leigh syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SURF1 protein in which other variant(s) (p.Lys291*) have been determined to be pathogenic (PMID: 9837813, 25111564, 27756633). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This frameshift has been observed in individual(s) with SURF1-related conditions (PMID: 33101984). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the SURF1 gene (p.Phe290Leufs*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the SURF1 protein and extend the protein by an uncertain number of additional amino acid residues. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

SURF1: PM2, PM3, PM4 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-136218800;