rs587781184

Variant names:

• chr9-133356390-C-T
• rs587598397
• NM_003172.4:c.54+10G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-133356390-C-T
• chrNW_009646201.1-182484-C-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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]

SURF2 (HGNC:11475): (surfeit 2) This gene shares a bidirectional promoter with surfeit 1 (SURF1; GeneID: 6834), which is located on the opposite strand. It encodes a conserved protein that is expressed in a variety of tissues. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: Splicing predictors support a deleterious 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 VariationId is 139379.
• 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003172.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SURF1	NM_003172.4	MANE Select	c.54+10G>A		intron	N/A	NP_003163.1
	SURF1	NM_001280787.1		c.-222+10G>A		intron	N/A	NP_001267716.1
	SURF2	NM_017503.5	MANE Select	c.-203C>T		upstream_gene	N/A	NP_059973.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SURF1	ENST00000371974.8	TSL:1 MANE Select	c.54+10G>A		intron	N/A	ENSP00000361042.3
	SURF1	ENST00000615505.4	TSL:1	c.-222+10G>A		intron	N/A	ENSP00000482067.1
	SURF1	ENST00000886676.1		c.54+10G>A		intron	N/A	ENSP00000556735.1

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

GnomAD2 exomes AF: 0.00535 AC: 127 AN: 23718 AF XY: 0.00554

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 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

African (AFR) AF: 0.000451 AC: 11 AN: 24364

American (AMR) AF: 0.00254 AC: 41 AN: 16130

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 341 AN: 18996

East Asian (EAS) AF: 0.00 AC: 0 AN: 27132

South Asian (SAS) AF: 0.00319 AC: 188 AN: 59020

European-Finnish (FIN) AF: 0.000198 AC: 6 AN: 30232

Middle Eastern (MID) AF: 0.00876 AC: 31 AN: 3538

European-Non Finnish (NFE) AF: 0.00427 AC: 4307 AN: 1008314

Other (OTH) AF: 0.00397 AC: 202 AN: 50912

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

African (AFR) AF: 0.000554 AC: 23 AN: 41488

American (AMR) AF: 0.00210 AC: 32 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00455 AC: 22 AN: 4834

European-Finnish (FIN) AF: 0.000191 AC: 2 AN: 10462

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00423 AC: 287 AN: 67880

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00420 Hom.: 0

Bravo AF: 0.00295

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Leigh syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		0.39
PromoterAI		-0.084	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs587598397; hg19: chr9-136223266;