rs587598397

Positions:

• chr9-133356390-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_003172.4(SURF1):​c.54+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,390,498 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (5 hom., cov: 34)
  • Exomes 𝑓: 0.0041 (14 hom.)
• Consequence: SURF1 NM_003172.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.389

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 -8 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 9-133356390-C-T is Benign according to our data. Variant chr9-133356390-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139379.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=2}. Variant chr9-133356390-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00285 (433/151860) while in subpopulation SAS AF= 0.00455 (22/4834). AF 95% confidence interval is 0.00383. There are 5 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SURF1	NM_003172.4	c.54+10G>A		intron_variant		ENST00000371974.8
SURF1	NM_001280787.1	c.-222+10G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SURF1	ENST00000371974.8	c.54+10G>A		intron_variant		1	NM_003172.4	P1
SURF1	ENST00000615505.4	c.-222+10G>A		intron_variant		1
SURF1	ENST00000463965.1	n.277+10G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 433 AN: 151754 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00423

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00535 AC: 127 AN: 23718 Hom.: 2 AF XY: 0.00554 AC XY: 80 AN XY: 14446

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.0213

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00373

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00499

Gnomad OTH exome AF: 0.00802

GnomAD4 exome AF: 0.00414 AC: 5127 AN: 1238638 Hom.: 14 Cov.: 36 AF XY: 0.00411 AC XY: 2493 AN XY: 607026

Gnomad4 AFR exome AF: 0.000451

Gnomad4 AMR exome AF: 0.00254

Gnomad4 ASJ exome AF: 0.0180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00319

Gnomad4 FIN exome AF: 0.000198

Gnomad4 NFE exome AF: 0.00427

Gnomad4 OTH exome AF: 0.00397

GnomAD4 genome AF: 0.00285 AC: 433 AN: 151860 Hom.: 5 Cov.: 34 AF XY: 0.00277 AC XY: 206 AN XY: 74242

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00210

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.00423

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00420 Hom.: 0

Bravo AF: 0.00295

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 02, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SURF1: BS2 -

Leigh syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 01, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.67		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587598397; hg19: chr9-136223266;