11-45805149-C-T

Position:

• chr11-45805149-C-T

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.-653C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 986,534 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (8 hom.)
• Consequence: SLC35C1 NM_018389.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0940

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=-0.69).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00342 (520/152074) while in subpopulation NFE AF= 0.00524 (356/67930). AF 95% confidence interval is 0.00479. There are 2 homozygotes in gnomad4. There are 268 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	Protein	UniProt
SLC35C1	NM_018389.5	c.-653C>T		5_prime_UTR_variant	1/2	ENST00000314134.4	NP_060859.4
SLC35C1	XM_011520203.4	c.-653C>T		5_prime_UTR_variant	1/2		XP_011518505.1
SLC35C1	NM_001145265.2	c.-32+632C>T		intron_variant			NP_001138737.1
SLC35C1	NM_001145266.1	c.-31-661C>T		intron_variant			NP_001138738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC35C1	ENST00000314134.4	c.-653C>T		5_prime_UTR_variant	1/2	1	NM_018389.5	ENSP00000313318	P4
SLC35C1	ENST00000442528.2	c.-32+632C>T		intron_variant		1		ENSP00000412408	A1
SLC35C1	ENST00000530471.1	c.-199C>T		5_prime_UTR_variant	1/2	3		ENSP00000432669
SLC35C1	ENST00000526817.2	c.-31-661C>T		intron_variant		2		ENSP00000432145	A1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 151956 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00524

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.00430 AC: 3587 AN: 834460 Hom.: 8 Cov.: 30 AF XY: 0.00435 AC XY: 1678 AN XY: 385492

Gnomad4 AFR exome AF: 0.000317

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000775

Gnomad4 EAS exome AF: 0.000275

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.00338

Gnomad4 NFE exome AF: 0.00452

Gnomad4 OTH exome AF: 0.00406

GnomAD4 genome AF: 0.00342 AC: 520 AN: 152074 Hom.: 2 Cov.: 33 AF XY: 0.00360 AC XY: 268 AN XY: 74346

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.00524

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00298 Hom.: 0

Bravo AF: 0.00258

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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 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, 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	-0.69
CADD	Benign	8.7
DANN	Benign	0.80

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: rs150274138; hg19: chr11-45826700;