rs41296099

Variant names:

• chr9-133352440-A-G
• rs41296099
• NM_003172.4:c.751+6T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

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
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• mitochondrial complex IV deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Charcot-Marie-Tooth disease type 4K

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with cardiomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SURF1	NM_003172.4	c.751+6T>C		splice_region_variant, intron_variant	Intron 7 of 8	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.424+6T>C		splice_region_variant, intron_variant	Intron 6 of 7		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8	c.751+6T>C		splice_region_variant, intron_variant	Intron 7 of 8	1	NM_003172.4	ENSP00000361042.3
SURF1	ENST00000615505.4	c.424+6T>C		splice_region_variant, intron_variant	Intron 6 of 7	1		ENSP00000482067.1
SURF1	ENST00000437995.1	n.661+6T>C		splice_region_variant, intron_variant	Intron 6 of 7	5
SURF1	ENST00000495952.5	n.741+6T>C		splice_region_variant, intron_variant	Intron 3 of 4	2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1998 AN: 152190 Hom.: 34 Cov.: 33

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

GnomAD2 exomes AF: 0.00533 AC: 1341 AN: 251470 AF XY: 0.00475

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 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.: 36 Cov.: 32 AF XY: 0.00349 AC XY: 2536 AN XY: 727232

African (AFR) AF: 0.0359 AC: 1203 AN: 33480

American (AMR) AF: 0.00698 AC: 312 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00369 AC: 318 AN: 86258

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53406

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5766

European-Non Finnish (NFE) AF: 0.00252 AC: 2797 AN: 1112012

Other (OTH) AF: 0.00661 AC: 399 AN: 60396

GnomAD4 genome AF: 0.0132 AC: 2004 AN: 152308 Hom.: 33 Cov.: 33 AF XY: 0.0129 AC XY: 960 AN XY: 74474

African (AFR) AF: 0.0379 AC: 1574 AN: 41560

American (AMR) AF: 0.00993 AC: 152 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00319 AC: 217 AN: 68026

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0105 Hom.: 0

Bravo AF: 0.0153

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00314

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SURF1: PP3, BS1, BS2 -

Dec 30, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 27, 2013

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. -

Leigh syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.81
PhyloP100		5.3
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs41296099; hg19: chr9-136219295;