rs781924765

chr9-133352086-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_003172.4(SURF1):c.808G>A(p.Glu270Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,610,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SURF1
NM_003172.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.64

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 Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_003172.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SURF1	NM_003172.4 linkuse as main transcript	c.808G>A	p.Glu270Lys	missense_variant	8/9	ENST00000371974.8
SURF1	NM_001280787.1 linkuse as main transcript	c.481G>A	p.Glu161Lys	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SURF1	ENST00000371974.8 linkuse as main transcript	c.808G>A	p.Glu270Lys	missense_variant	8/9	1	NM_003172.4	P1	Q15526-1
SURF1	ENST00000615505.4 linkuse as main transcript	c.481G>A	p.Glu161Lys	missense_variant	7/8	1
SURF1	ENST00000437995.1 linkuse as main transcript	n.718G>A		non_coding_transcript_exon_variant	7/8	5
SURF1	ENST00000495952.5 linkuse as main transcript	n.798G>A		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000245

AC:

AN:

244630

Hom.:

AF XY:

0.0000302

AC XY:

AN XY:

132350

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000362

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1458636

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

725258

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.808G>A (p.E270K) alteration is located in exon 8 (coding exon 8) of the SURF1 gene. This alteration results from a G to A substitution at nucleotide position 808, causing the glutamic acid (E) at amino acid position 270 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Leigh syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 270 of the SURF1 protein (p.Glu270Lys). This variant is present in population databases (rs781924765, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SURF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 526789). 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 expected to disrupt SURF1 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.35

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0040

D;.

Sift4G

Benign

0.062

T;T

Polyphen

0.58

P;.

Vest4

0.89

MVP

0.86

MPC

0.098

ClinPred

0.55

GERP RS

5.4

Varity_R

0.42

gMVP

0.89

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

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