11-45810958-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018389.5(SLC35C1):c.718A>G(p.Ile240Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,612,700 control chromosomes in the GnomAD database, including 10,560 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I240L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (1487 hom., cov: 34)
  • Exomes 𝑓: 0.11 (9073 hom.)
• Consequence: SLC35C1 NM_018389.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.592

Genes affected

SLC35C1 (HGNC:20197): (solute carrier family 35 member C1) This gene encodes a GDP-fucose transporter that is found in the Golgi apparatus. Mutations in this gene result in congenital disorder of glycosylation type IIc. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012888312).
• BP6: Variant 11-45810958-A-G is Benign according to our data. Variant chr11-45810958-A-G is described in ClinVar as [Benign]. Clinvar id is 95905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-45810958-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC35C1	NM_018389.5	c.718A>G	p.Ile240Val	missense_variant	2/2	ENST00000314134.4
SLC35C1	NM_001145265.2	c.679A>G	p.Ile227Val	missense_variant	3/3
SLC35C1	NM_001145266.1	c.679A>G	p.Ile227Val	missense_variant	3/3
SLC35C1	XM_011520202.3	c.211A>G	p.Ile71Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC35C1	ENST00000314134.4	c.718A>G	p.Ile240Val	missense_variant	2/2	1	NM_018389.5	P4
SLC35C1	ENST00000442528.2	c.679A>G	p.Ile227Val	missense_variant	3/3	1		A1
SLC35C1	ENST00000526817.2	c.679A>G	p.Ile227Val	missense_variant	3/3	2		A1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19325 AN: 152172 Hom.: 1488 Cov.: 34

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.0826

Gnomad AMR AF: 0.0965

Gnomad ASJ AF: 0.0974

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.106

GnomAD3 exomes AF: 0.0916 AC: 22925 AN: 250400 Hom.: 1401 AF XY: 0.0874 AC XY: 11852 AN XY: 135534

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.0591

Gnomad ASJ exome AF: 0.0907

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.0232

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.0953

GnomAD4 exome AF: 0.105 AC: 153822 AN: 1460410 Hom.: 9073 Cov.: 38 AF XY: 0.102 AC XY: 74233 AN XY: 726578

Gnomad4 AFR exome AF: 0.208

Gnomad4 AMR exome AF: 0.0608

Gnomad4 ASJ exome AF: 0.0913

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0242

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.127 AC: 19337 AN: 152290 Hom.: 1487 Cov.: 34 AF XY: 0.125 AC XY: 9279 AN XY: 74470

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.0962

Gnomad4 ASJ AF: 0.0974

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.104

Alfa AF: 0.103 Hom.: 1965

Bravo AF: 0.130

TwinsUK AF: 0.122 AC: 454

ALSPAC AF: 0.118 AC: 454

ESP6500AA AF: 0.206 AC: 906

ESP6500EA AF: 0.112 AC: 959

ExAC AF: 0.0941 AC: 11426

EpiCase AF: 0.108

EpiControl AF: 0.102

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2016	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. -

Leukocyte adhesion deficiency type II Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	0.85
Dann	Benign	0.50
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.063
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.017
MPC		0.46
ClinPred		0.00030	T
GERP RS		1.1
Varity_R		0.031
gMVP		0.32

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: rs7130656; hg19: chr11-45832509; COSMIC: COSV58479467; COSMIC: COSV58479467;