rs28615629

Variant names:

• chr9-133354702-A-G
• rs28615629
• ENST00000615505.4:c.-48T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001280787.1(SURF1):​c.-48T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0399 in 1,613,358 control chromosomes in the GnomAD database, including 1,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (194 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1327 hom.)
• Consequence: SURF1 NM_001280787.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.34
• Publications: 8 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=-0.51).
• BP6: Variant 9-133354702-A-G is Benign according to our data. Variant chr9-133354702-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001280787.1. 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.280T>C	p.Leu94Leu	synonymous	Exon 4 of 9	NP_003163.1	Q15526-1
	SURF1	NM_001280787.1		c.-48T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 8	NP_001267716.1	A0A087WYS9
	SURF1	NM_001280787.1		c.-48T>C		5_prime_UTR	Exon 3 of 8	NP_001267716.1	A0A087WYS9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SURF1	ENST00000615505.4	TSL:1	c.-48T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 8	ENSP00000482067.1	A0A087WYS9
	SURF1	ENST00000371974.8	TSL:1 MANE Select	c.280T>C	p.Leu94Leu	synonymous	Exon 4 of 9	ENSP00000361042.3	Q15526-1
	SURF1	ENST00000615505.4	TSL:1	c.-48T>C		5_prime_UTR	Exon 3 of 8	ENSP00000482067.1	A0A087WYS9

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7255 AN: 152016 Hom.: 194 Cov.: 32

Gnomad AFR AF: 0.0670

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0733

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0369 AC: 9278 AN: 251274 AF XY: 0.0369

Gnomad AFR exome AF: 0.0638

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0430

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0680

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0416

GnomAD4 exome AF: 0.0391 AC: 57080 AN: 1461224 Hom.: 1327 Cov.: 32 AF XY: 0.0385 AC XY: 27974 AN XY: 726930

African (AFR) AF: 0.0644 AC: 2156 AN: 33480

American (AMR) AF: 0.0223 AC: 998 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 1065 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0223 AC: 1921 AN: 86248

European-Finnish (FIN) AF: 0.0667 AC: 3523 AN: 52852

Middle Eastern (MID) AF: 0.0516 AC: 294 AN: 5696

European-Non Finnish (NFE) AF: 0.0403 AC: 44819 AN: 1112008

Other (OTH) AF: 0.0381 AC: 2302 AN: 60380

GnomAD4 genome AF: 0.0477 AC: 7260 AN: 152134 Hom.: 194 Cov.: 32 AF XY: 0.0484 AC XY: 3598 AN XY: 74358

African (AFR) AF: 0.0669 AC: 2778 AN: 41496

American (AMR) AF: 0.0361 AC: 552 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 140 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0185 AC: 89 AN: 4814

European-Finnish (FIN) AF: 0.0733 AC: 776 AN: 10584

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0399 AC: 2713 AN: 67996

Other (OTH) AF: 0.0407 AC: 86 AN: 2112

Alfa AF: 0.0424 Hom.: 30

Bravo AF: 0.0450

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.0388

EpiControl AF: 0.0375

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Leigh syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.3
DANN	Benign	0.80
PhyloP100		2.3
Mutation Taster		=99/1	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: rs28615629; hg19: chr9-136221557;