rs28615629

Positions:

chr9-133354702-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003172.4(SURF1):c.280T>C(p.Leu94=) variant causes a synonymous 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L94L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.048 ( 194 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1327 hom. )

Consequence

SURF1
NM_003172.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.34

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 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].

BP7

Synonymous conserved (PhyloP=2.34 with no splicing effect.

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/exons	MANE	UniProt
SURF1	NM_003172.4 linkuse as main transcript	c.280T>C	p.Leu94=	synonymous_variant	4/9	ENST00000371974.8
SURF1	NM_001280787.1 linkuse as main transcript	c.-48T>C		5_prime_UTR_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SURF1	ENST00000371974.8 linkuse as main transcript	c.280T>C	p.Leu94=	synonymous_variant	4/9	1	NM_003172.4	P1	Q15526-1
SURF1	ENST00000615505.4 linkuse as main transcript	c.-48T>C		5_prime_UTR_variant	3/8	1
SURF1	ENST00000437995.1 linkuse as main transcript	n.226T>C		non_coding_transcript_exon_variant	3/8	5

Frequencies

GnomAD3 genomes

AF:

0.0477

AC:

7255

AN:

152016

Hom.:

194

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0385

AC XY:

27974

AN XY:

726930

show subpopulations

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.:

AF XY:

0.0484

AC XY:

3598

AN XY:

74358

show subpopulations

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.:

Bravo

AF:

0.0450

Asia WGS

AF:

0.0170

AC:

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

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2011	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Leigh syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2016	- -

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

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