9-133352593-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BA1

The NM_003172.4(SURF1):c.604G>C(p.Asp202His) variant causes a missense change. The variant allele was found at a frequency of 0.00514 in 1,614,146 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0068 ( 80 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 359 hom. )

Consequence

SURF1
NM_003172.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 5.82

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 Benign. Variant got -11 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0063804686).

BP6

Variant 9-133352593-C-G is Benign according to our data. Variant chr9-133352593-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139375.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SURF1	NM_003172.4 link	c.604G>C	p.Asp202His	missense_variant	Exon 7 of 9	ENST00000371974.8	NP_003163.1	Q15526-1E5KRX5
SURF1	NM_001280787.1 link	c.277G>C	p.Asp93His	missense_variant	Exon 6 of 8		NP_001267716.1	Q15526A0A087WYS9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SURF1	ENST00000371974.8 link	c.604G>C	p.Asp202His	missense_variant	Exon 7 of 9	1	NM_003172.4	ENSP00000361042.3	Q15526-1
SURF1	ENST00000615505.4 link	c.277G>C	p.Asp93His	missense_variant	Exon 6 of 8	1		ENSP00000482067.1	A0A087WYS9
SURF1	ENST00000437995.1 link	n.514G>C		non_coding_transcript_exon_variant	Exon 6 of 8	5
SURF1	ENST00000495952.5 link	n.594G>C		non_coding_transcript_exon_variant	Exon 3 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.00687

AC:

1045

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00812

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.0143

AC:

3584

AN:

251146

Hom.:

230

AF XY:

0.0129

AC XY:

1756

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.0152

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.153

Gnomad SAS exome

AF:

0.00265

Gnomad FIN exome

AF:

0.00143

Gnomad NFE exome

AF:

0.000502

Gnomad OTH exome

AF:

0.00750

GnomAD4 exome

AF:

0.00496

AC:

7253

AN:

1461848

Hom.:

359

Cov.:

AF XY:

0.00482

AC XY:

3505

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.0142

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.126

Gnomad4 SAS exome

AF:

0.00376

Gnomad4 FIN exome

AF:

0.00131

Gnomad4 NFE exome

AF:

0.000517

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.00685

AC:

1043

AN:

152298

Hom.:

Cov.:

AF XY:

0.00745

AC XY:

555

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00147

Gnomad4 AMR

AF:

0.00810

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.151

Gnomad4 SAS

AF:

0.00540

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00758

Bravo

AF:

0.00808

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0132

AC:

1601

Asia WGS

AF:

0.0650

AC:

226

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 09, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Jun 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-4.0

D;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.97

D;.

Vest4

0.24

MPC

0.17

ClinPred

0.027

GERP RS

5.4

Varity_R

0.46

gMVP

0.64

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