11-45805169-T-G

Position:

• chr11-45805169-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_018389.5(SLC35C1):​c.-633T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 990,510 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (6 hom.)
• Consequence: SLC35C1 NM_018389.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -6.70

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00179 (272/151792) while in subpopulation AMR AF= 0.00524 (80/15278). AF 95% confidence interval is 0.00431. There are 2 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC35C1	NM_018389.5	c.-633T>G		5_prime_UTR_variant	1/2	ENST00000314134.4
SLC35C1	XM_011520203.4	c.-633T>G		5_prime_UTR_variant	1/2
SLC35C1	NM_001145265.2	c.-31-641T>G		intron_variant
SLC35C1	NM_001145266.1	c.-31-641T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC35C1	ENST00000314134.4	c.-633T>G		5_prime_UTR_variant	1/2	1	NM_018389.5	P4
SLC35C1	ENST00000442528.2	c.-31-641T>G		intron_variant		1		A1
SLC35C1	ENST00000530471.1	c.-179T>G		5_prime_UTR_variant	1/2	3
SLC35C1	ENST00000526817.2	c.-31-641T>G		intron_variant		2		A1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 151676 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000800

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00217

Gnomad OTH AF: 0.00288

GnomAD4 exome AF: 0.00274 AC: 2296 AN: 838718 Hom.: 6 Cov.: 30 AF XY: 0.00274 AC XY: 1064 AN XY: 387808

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.00477

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00287

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00179 AC: 272 AN: 151792 Hom.: 2 Cov.: 33 AF XY: 0.00160 AC XY: 119 AN XY: 74192

Gnomad4 AFR AF: 0.000797

Gnomad4 AMR AF: 0.00524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.00217

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00250 Hom.: 0

Bravo AF: 0.00226

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leukocyte adhesion deficiency type II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.037
DANN	Benign	0.71

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: rs566857902; hg19: chr11-45826720;