chr9-133351795-A-G

Variant names:

• chr9-133351795-A-G
• rs4962133
• NM_003172.4:c.*118T>C

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -0.229
• Publications: 5 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]

SURF1 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• mitochondrial complex IV deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4K

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with cardiomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.*118T>C		3_prime_UTR	Exon 9 of 9	NP_003163.1	Q15526-1
	SURF1	NM_001280787.1		c.*118T>C		downstream_gene	N/A	NP_001267716.1	A0A087WYS9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SURF1	ENST00000371974.8	TSL:1 MANE Select	c.*118T>C		3_prime_UTR	Exon 9 of 9	ENSP00000361042.3	Q15526-1
	SURF1	ENST00000615505.4	TSL:1	c.*118T>C		downstream_gene	N/A	ENSP00000482067.1	A0A087WYS9
	SURF1	ENST00000886676.1		c.*118T>C		downstream_gene	N/A	ENSP00000556735.1

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

African (AFR) AF: 0.0126 AC: 301 AN: 23898

American (AMR) AF: 0.0367 AC: 1287 AN: 35064

Ashkenazi Jewish (ASJ) AF: 0.0765 AC: 1727 AN: 22570

East Asian (EAS) AF: 0.0238 AC: 813 AN: 34092

South Asian (SAS) AF: 0.0212 AC: 1510 AN: 71218

European-Finnish (FIN) AF: 0.0599 AC: 2581 AN: 43084

Middle Eastern (MID) AF: 0.0566 AC: 267 AN: 4720

European-Non Finnish (NFE) AF: 0.0850 AC: 60559 AN: 712784

Other (OTH) AF: 0.0698 AC: 3129 AN: 44822

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

African (AFR) AF: 0.0157 AC: 651 AN: 41570

American (AMR) AF: 0.0477 AC: 730 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0796 AC: 276 AN: 3468

East Asian (EAS) AF: 0.0191 AC: 99 AN: 5188

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4830

European-Finnish (FIN) AF: 0.0592 AC: 629 AN: 10622

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0870 AC: 5917 AN: 68024

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0710 Hom.: 36

Bravo AF: 0.0546

Asia WGS AF: 0.0350 AC: 122 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.72
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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