rs28615629

Variant names:

• chr9-133354702-A-G
• rs28615629
• ENST00000615505.4:c.-48T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000615505.4(SURF1):​c.-48T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0399 in 1,613,358 control chromosomes in the GnomAD database, including 1,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (194 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1327 hom.)
• Consequence: SURF1 ENST00000615505.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.34
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 9-133354702-A-G is Benign according to our data. Variant chr9-133354702-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SURF1	NM_003172.4	c.280T>C	p.Leu94Leu	synonymous_variant	Exon 4 of 9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.-48T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 8		NP_001267716.1
SURF1	NM_001280787.1	c.-48T>C		5_prime_UTR_variant	Exon 3 of 8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000615505.4	c.-48T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 8	1		ENSP00000482067.1
SURF1	ENST00000371974.8	c.280T>C	p.Leu94Leu	synonymous_variant	Exon 4 of 9	1	NM_003172.4	ENSP00000361042.3
SURF1	ENST00000615505.4	c.-48T>C		5_prime_UTR_variant	Exon 3 of 8	1		ENSP00000482067.1
SURF1	ENST00000437995.1	n.226T>C		non_coding_transcript_exon_variant	Exon 3 of 8	5

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7255 AN: 152016 Hom.: 194 Cov.: 32

Gnomad AFR AF: 0.0670

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0733

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0369 AC: 9278 AN: 251274 AF XY: 0.0369

Gnomad AFR exome AF: 0.0638

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0430

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0680

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0416

GnomAD4 exome AF: 0.0391 AC: 57080 AN: 1461224 Hom.: 1327 Cov.: 32 AF XY: 0.0385 AC XY: 27974 AN XY: 726930

African (AFR) AF: 0.0644 AC: 2156 AN: 33480

American (AMR) AF: 0.0223 AC: 998 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 1065 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0223 AC: 1921 AN: 86248

European-Finnish (FIN) AF: 0.0667 AC: 3523 AN: 52852

Middle Eastern (MID) AF: 0.0516 AC: 294 AN: 5696

European-Non Finnish (NFE) AF: 0.0403 AC: 44819 AN: 1112008

Other (OTH) AF: 0.0381 AC: 2302 AN: 60380

GnomAD4 genome AF: 0.0477 AC: 7260 AN: 152134 Hom.: 194 Cov.: 32 AF XY: 0.0484 AC XY: 3598 AN XY: 74358

African (AFR) AF: 0.0669 AC: 2778 AN: 41496

American (AMR) AF: 0.0361 AC: 552 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 140 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0185 AC: 89 AN: 4814

European-Finnish (FIN) AF: 0.0733 AC: 776 AN: 10584

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0399 AC: 2713 AN: 67996

Other (OTH) AF: 0.0407 AC: 86 AN: 2112

Alfa AF: 0.0424 Hom.: 30

Bravo AF: 0.0450

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.0388

EpiControl AF: 0.0375

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Dec 18, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SURF1 c.280T>C (p.Leu94Leu) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and ESE sites at the locus are not predicted to be affected. However, these predictions have yet to be confirmed by functional studies. This variant was found in 10613/277080 control chromosomes (258 homozygotes) at a frequency of 0.038303, which is approximately 22 times the estimated maximal expected allele frequency of a pathogenic SURF1 variant (0.0017678), strongly suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign or benign. Taken together, this variant is classified as benign. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 06, 2011

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:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 25, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.3
DANN	Benign	0.80
PhyloP100		2.3
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28615629; hg19: chr9-136221557;