chr9-133352440-A-G

Position:

chr9-133352440-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_003172.4(SURF1):c.751+6T>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00447 in 1,614,184 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 33 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 36 hom. )

Consequence

SURF1
NM_003172.4 splice_region, intron

Scores

Splicing: ADA: 0.9977

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.33

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 9-133352440-A-G is Benign according to our data. Variant chr9-133352440-A-G is described in ClinVar as [Benign]. Clinvar id is 139376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133352440-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0132 (2004/152308) while in subpopulation AFR AF= 0.0379 (1574/41560). AF 95% confidence interval is 0.0363. There are 33 homozygotes in gnomad4. There are 960 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SURF1	NM_003172.4 linkuse as main transcript	c.751+6T>C		splice_region_variant, intron_variant		ENST00000371974.8	NP_003163.1	Q15526-1E5KRX5
SURF1	NM_001280787.1 linkuse as main transcript	c.424+6T>C		splice_region_variant, intron_variant			NP_001267716.1	Q15526A0A087WYS9

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
SURF1	ENST00000371974.8 linkuse as main transcript	c.751+6T>C	splice_region_variant, intron_variant	1	NM_003172.4	ENSP00000361042.3	Q15526-1
SURF1	ENST00000615505.4 linkuse as main transcript	c.424+6T>C	splice_region_variant, intron_variant	1		ENSP00000482067.1	A0A087WYS9
SURF1	ENST00000437995.1 linkuse as main transcript	n.661+6T>C	splice_region_variant, intron_variant	5
SURF1	ENST00000495952.5 linkuse as main transcript	n.741+6T>C	splice_region_variant, intron_variant	2

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1998

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0378

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00995

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00319

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.00533

AC:

1341

AN:

251470

Hom.:

AF XY:

0.00475

AC XY:

645

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0382

Gnomad AMR exome

AF:

0.00601

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:

0.00305

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00356

AC:

5205

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

2536

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0359

Gnomad4 AMR exome

AF:

0.00698

Gnomad4 ASJ exome

AF:

0.000957

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00369

Gnomad4 FIN exome

AF:

0.000562

Gnomad4 NFE exome

AF:

0.00252

Gnomad4 OTH exome

AF:

0.00661

GnomAD4 genome

AF:

0.0132

AC:

2004

AN:

152308

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

960

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0379

Gnomad4 AMR

AF:

0.00993

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00319

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.0153

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00314

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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	Jan 01, 2023	SURF1: PP3, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2013

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. -

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

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.63

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.29

Position offset: -25

DS_DL_spliceai

0.63

Position offset: 6

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