9-133352593-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BA1

The NM_003172.4(SURF1):c.604G>C(p.Asp202His) variant causes a missense change. The variant allele was found at a frequency of 0.00514 in 1,614,146 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D202D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (80 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (359 hom.)
• Consequence: SURF1 NM_003172.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 5.82

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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_003172.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0063804686).
• BP6: Variant 9-133352593-C-G is Benign according to our data. Variant chr9-133352593-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139375.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SURF1	NM_003172.4	c.604G>C	p.Asp202His	missense_variant	7/9	ENST00000371974.8
SURF1	NM_001280787.1	c.277G>C	p.Asp93His	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SURF1	ENST00000371974.8	c.604G>C	p.Asp202His	missense_variant	7/9	1	NM_003172.4	P1
SURF1	ENST00000615505.4	c.277G>C	p.Asp93His	missense_variant	6/8	1
SURF1	ENST00000437995.1	n.514G>C		non_coding_transcript_exon_variant	6/8	5
SURF1	ENST00000495952.5	n.594G>C		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes AF: 0.00687 AC: 1045 AN: 152180 Hom.: 80 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0143 AC: 3584 AN: 251146 Hom.: 230 AF XY: 0.0129 AC XY: 1756 AN XY: 135832

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00496 AC: 7253 AN: 1461848 Hom.: 359 Cov.: 32 AF XY: 0.00482 AC XY: 3505 AN XY: 727208

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.00376

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.000517

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00685 AC: 1043 AN: 152298 Hom.: 80 Cov.: 33 AF XY: 0.00745 AC XY: 555 AN XY: 74458

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00810

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.00540

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00758

Bravo AF: 0.00808

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0132 AC: 1601

Asia WGS AF: 0.0650 AC: 226 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Leigh syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.97	D;.
Vest4		0.24
MPC		0.17
ClinPred		0.027	T
GERP RS		5.4
Varity_R		0.46
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72619327; hg19: chr9-136219448; COSMIC: COSV59298602; COSMIC: COSV59298602;