rs28615629

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001280787.1(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 NM_001280787.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.34

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 139373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133354702-A-G is described in Lovd as [Benign].
• 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

GnomAD3 exomes AF: 0.0369 AC: 9278 AN: 251274 Hom.: 230 AF XY: 0.0369 AC XY: 5007 AN XY: 135830

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 SAS exome AF: 0.0223

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

Gnomad4 AFR exome AF: 0.0644

Gnomad4 AMR exome AF: 0.0223

Gnomad4 ASJ exome AF: 0.0407

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0223

Gnomad4 FIN exome AF: 0.0667

Gnomad4 NFE exome AF: 0.0403

Gnomad4 OTH exome AF: 0.0381

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

Gnomad4 AFR AF: 0.0669

Gnomad4 AMR AF: 0.0361

Gnomad4 ASJ AF: 0.0403

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0185

Gnomad4 FIN AF: 0.0733

Gnomad4 NFE AF: 0.0399

Gnomad4 OTH AF: 0.0407

Alfa AF: 0.0420 Hom.: 22

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

-

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. -

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

- -

Leigh syndrome Benign:2

Feb 04, 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 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

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

Other links and lift over

dbSNP: rs28615629; hg19: chr9-136221557;