Variant 9-133351945-T-TA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_003172.4(SURF1):c.870_871insT(p.Lys291Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SURF1
NM_003172.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -0.396

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-133351945-T-TA is Pathogenic according to our data. Variant chr9-133351945-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 520829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SURF1	NM_003172.4 linkuse as main transcript	c.870_871insT	p.Lys291Ter	frameshift_variant	9/9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1 linkuse as main transcript	c.543_544insT	p.Lys182Ter	frameshift_variant	8/8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8 linkuse as main transcript	c.870_871insT	p.Lys291Ter	frameshift_variant	9/9	1	NM_003172.4	ENSP00000361042	P1	Q15526-1
SURF1	ENST00000615505.4 linkuse as main transcript	c.543_544insT	p.Lys182Ter	frameshift_variant	8/8	1		ENSP00000482067
SURF1	ENST00000437995.1 linkuse as main transcript	n.780_781insT		non_coding_transcript_exon_variant	8/8	5
SURF1	ENST00000495952.5 linkuse as main transcript	n.860_861insT		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250790

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461620

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1998	- -

Leigh syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 09, 2023	Variant summary: SURF1 c.870dupT (p.Lys291X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4e-06 in 250790 control chromosomes (gnomAD). c.870dupT has been reported in the literature as a biallelic genotype in multiple individuals affected with Leigh Syndrome (e.g. Tiranti_1998, Ribeiro_2016, Kose_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact of the variant on protein function found that COX levels in homozygous tissues were 10%-15% of normal (Tiranti_1998, Tiranti_1999). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 05, 2023	This variant is present in population databases (rs782061187, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 520829). This variant is also known as c.868_869insT, 868insT, K290X. This premature translational stop signal has been observed in individual(s) with clinical features of mitochondrial complex IV deficiency (PMID: 9837813, 25111564, 27756633). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Lys291*) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the SURF1 protein. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over