9-133351795-A-G

Variant summary

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

The NM_003172.4(SURF1):c.*118T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0705 in 1,144,576 control chromosomes in the GnomAD database, including 3,318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (333 hom., cov: 33)
  • Exomes 𝑓: 0.073 (2985 hom.)
• Consequence: SURF1 NM_003172.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.229

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=-0.81).
• BP6: Variant 9-133351795-A-G is Benign according to our data. Variant chr9-133351795-A-G is described in ClinVar as [Benign]. Clinvar id is 912544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SURF1	NM_003172.4	c.*118T>C		3_prime_UTR_variant	9/9	ENST00000371974.8
SURF1	NM_001280787.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SURF1	ENST00000371974.8	c.*118T>C		3_prime_UTR_variant	9/9	1	NM_003172.4	P1
SURF1	ENST00000615505.4			downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0563 AC: 8573 AN: 152206 Hom.: 334 Cov.: 33

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0477

Gnomad ASJ AF: 0.0796

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.0592

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0870

Gnomad OTH AF: 0.0602

GnomAD4 exome AF: 0.0727 AC: 72174 AN: 992252 Hom.: 2985 Cov.: 13 AF XY: 0.0708 AC XY: 35690 AN XY: 503816

Gnomad4 AFR exome AF: 0.0126

Gnomad4 AMR exome AF: 0.0367

Gnomad4 ASJ exome AF: 0.0765

Gnomad4 EAS exome AF: 0.0238

Gnomad4 SAS exome AF: 0.0212

Gnomad4 FIN exome AF: 0.0599

Gnomad4 NFE exome AF: 0.0850

Gnomad4 OTH exome AF: 0.0698

GnomAD4 genome AF: 0.0563 AC: 8570 AN: 152324 Hom.: 333 Cov.: 33 AF XY: 0.0550 AC XY: 4094 AN XY: 74490

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.0477

Gnomad4 ASJ AF: 0.0796

Gnomad4 EAS AF: 0.0191

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.0592

Gnomad4 NFE AF: 0.0870

Gnomad4 OTH AF: 0.0591

Alfa AF: 0.0710 Hom.: 36

Bravo AF: 0.0546

Asia WGS AF: 0.0350 AC: 122 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.1
Dann	Benign	0.72

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: rs4962133; hg19: chr9-136218650; COSMIC: COSV59297594; COSMIC: COSV59297594;