chr9-133354897-G-C

Position:

chr9-133354897-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_003172.4(SURF1):c.167C>G(p.Ala56Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,613,944 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 28 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 35 hom. )

Consequence

SURF1
NM_003172.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.737

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:

SURF1 (HGNC:):

SURF1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 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=0.0028353333).

BP6

Variant 9-133354897-G-C is Benign according to our data. Variant chr9-133354897-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 139372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133354897-G-C is described in UniProt as null. Variant chr9-133354897-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0123 (1871/152268) while in subpopulation AFR AF= 0.0354 (1468/41526). AF 95% confidence interval is 0.0338. There are 28 homozygotes in gnomad4. There are 892 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SURF1	NM_003172.4 linkuse as main transcript	c.167C>G	p.Ala56Gly	missense_variant	3/9	ENST00000371974.8	NP_003163.1	Q15526-1E5KRX5
SURF1	NM_001280787.1 linkuse as main transcript	c.-161C>G		5_prime_UTR_variant	2/8		NP_001267716.1	Q15526A0A087WYS9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SURF1	ENST00000371974.8 linkuse as main transcript	c.167C>G	p.Ala56Gly	missense_variant	3/9	1	NM_003172.4	ENSP00000361042.3	Q15526-1
SURF1	ENST00000615505.4 linkuse as main transcript	c.-161C>G		5_prime_UTR_variant	2/8	1		ENSP00000482067.1	A0A087WYS9
SURF1	ENST00000437995.1 linkuse as main transcript	n.113C>G		non_coding_transcript_exon_variant	2/8	5

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1866

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0353

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00837

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00316

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.00510

AC:

1283

AN:

251400

Hom.:

AF XY:

0.00458

AC XY:

622

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0358

Gnomad AMR exome

AF:

0.00564

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00349

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00302

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00348

AC:

5088

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00341

AC XY:

2481

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.0339

Gnomad4 AMR exome

AF:

0.00631

Gnomad4 ASJ exome

AF:

0.000957

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00368

Gnomad4 FIN exome

AF:

0.000564

Gnomad4 NFE exome

AF:

0.00251

Gnomad4 OTH exome

AF:

0.00639

GnomAD4 genome

AF:

0.0123

AC:

1871

AN:

152268

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

892

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0354

Gnomad4 AMR

AF:

0.00836

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00316

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.000653

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.0320

AC:

141

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00544

AC:

661

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SURF1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	This variant is associated with the following publications: (PMID: 22488715, 27884173, 16091512) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 18, 2022

- -

Leigh syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.90

DANN

Benign

0.74

DEOGEN2

Benign

0.29

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.35

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.70

REVEL

Benign

0.12

Sift

Benign

0.24

Sift4G

Benign

0.33

Polyphen

0.32

Vest4

0.20

MVP

0.68

MPC

0.031

ClinPred

0.0030

GERP RS

2.1

Varity_R

0.032

gMVP

0.46

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