9-133354897-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003172.4(SURF1):c.167C>G(p.Ala56Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,613,944 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A56A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (35 hom.)
• Consequence: SURF1 NM_003172.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.737

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 -18 ACMG points.

• PM1: In a chain Surfeit locus protein 1 (size 299) in uniprot entity SURF1_HUMAN there are 46 pathogenic changes around while only 10 benign (82%) in NM_003172.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0028353333).
• BP6: Variant 9-133354897-G-C is Benign according to our data. Variant chr9-133354897-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 139372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133354897-G-C is described in UniProt as null. Variant chr9-133354897-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0123 (1871/152268) while in subpopulation AFR AF= 0.0354 (1468/41526). AF 95% confidence interval is 0.0338. There are 28 homozygotes in gnomad4. There are 892 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SURF1	NM_003172.4	c.167C>G	p.Ala56Gly	missense_variant	3/9	ENST00000371974.8
SURF1	NM_001280787.1	c.-161C>G		5_prime_UTR_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SURF1	ENST00000371974.8	c.167C>G	p.Ala56Gly	missense_variant	3/9	1	NM_003172.4	P1
SURF1	ENST00000615505.4	c.-161C>G		5_prime_UTR_variant	2/8	1
SURF1	ENST00000437995.1	n.113C>G		non_coding_transcript_exon_variant	2/8	5

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1866 AN: 152150 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00837

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00510 AC: 1283 AN: 251400 Hom.: 19 AF XY: 0.00458 AC XY: 622 AN XY: 135880

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.00564

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00349

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00348 AC: 5088 AN: 1461676 Hom.: 35 Cov.: 32 AF XY: 0.00341 AC XY: 2481 AN XY: 727138

Gnomad4 AFR exome AF: 0.0339

Gnomad4 AMR exome AF: 0.00631

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00368

Gnomad4 FIN exome AF: 0.000564

Gnomad4 NFE exome AF: 0.00251

Gnomad4 OTH exome AF: 0.00639

GnomAD4 genome AF: 0.0123 AC: 1871 AN: 152268 Hom.: 28 Cov.: 32 AF XY: 0.0120 AC XY: 892 AN XY: 74446

Gnomad4 AFR AF: 0.0354

Gnomad4 AMR AF: 0.00836

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00316

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.000653 Hom.: 0

Bravo AF: 0.0141

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.0320 AC: 141

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00544 AC: 661

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	This variant is associated with the following publications: (PMID: 22488715, 27884173, 16091512) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	SURF1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 18, 2022

- -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	0.90
Dann	Benign	0.74
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.35	N
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.12
Sift	Benign	0.24	T
Sift4G	Benign	0.33	T
Polyphen		0.32	B
Vest4		0.20
MVP		0.68
MPC		0.031
ClinPred		0.0030	T
GERP RS		2.1
Varity_R		0.032
gMVP		0.46

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: rs116779216; hg19: chr9-136221752;