9-133356570-G-C

Variant names:

• chr9-133356570-G-C
• rs587711454
• ENST00000371964:c.-23G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017503.5(SURF2):​c.-23G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000836 in 1,514,910 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (24 hom.)
• Consequence: SURF2 NM_017503.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00400

Genes affected

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]

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=-0.82).
• BP6: Variant 9-133356570-G-C is Benign according to our data. Variant chr9-133356570-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1198865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000732 (997/1362724) while in subpopulation AMR AF= 0.0226 (772/34128). AF 95% confidence interval is 0.0213. There are 24 homozygotes in gnomad4_exome. There are 423 alleles in male gnomad4_exome subpopulation. Median coverage is 38. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SURF2	NM_017503.5	c.-23G>C		5_prime_UTR_variant	Exon 1 of 6	ENST00000371964.5	NP_059973.4
SURF2	NM_001278928.2	c.-23G>C		5_prime_UTR_variant	Exon 1 of 6		NP_001265857.1
SURF1	NM_003172.4	c.-117C>G		upstream_gene_variant		ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.-392C>G		upstream_gene_variant			NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SURF2	ENST00000371964	c.-23G>C		5_prime_UTR_variant	Exon 1 of 6	1	NM_017503.5	ENSP00000361032.4
SURF1	ENST00000371974.8	c.-117C>G		upstream_gene_variant		1	NM_003172.4	ENSP00000361042.3

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 270 AN: 152078 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00751

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00529 AC: 584 AN: 110308 Hom.: 13 AF XY: 0.00378 AC XY: 232 AN XY: 61346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00967

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.000732 AC: 997 AN: 1362724 Hom.: 24 Cov.: 38 AF XY: 0.000629 AC XY: 423 AN XY: 672138

Gnomad4 AFR exome AF: 0.000141

Gnomad4 AMR exome AF: 0.0226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00385

Gnomad4 SAS exome AF: 0.0000258

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000121

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152186 Hom.: 2 Cov.: 32 AF XY: 0.00189 AC XY: 141 AN XY: 74410

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00753

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00371

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 03, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.7
DANN	Benign	0.55

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: rs587711454; hg19: chr9-136223446; COSMIC: COSV64332528; COSMIC: COSV64332528;