rs141379070

Positions:

• chr11-45806323-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_018389.5(SLC35C1):​c.522C>T​(p.Cys174Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,612,664 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (13 hom.)
• Consequence: SLC35C1 NM_018389.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.277

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 11-45806323-C-T is Benign according to our data. Variant chr11-45806323-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 304739.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr11-45806323-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.277 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00273 (415/152248) while in subpopulation NFE AF= 0.0024 (163/67998). AF 95% confidence interval is 0.0021. There are 1 homozygotes in gnomad4. There are 237 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC35C1	NM_018389.5	c.522C>T	p.Cys174Cys	synonymous_variant	1/2	ENST00000314134.4	NP_060859.4
SLC35C1	NM_001145265.2	c.483C>T	p.Cys161Cys	synonymous_variant	2/3		NP_001138737.1
SLC35C1	NM_001145266.1	c.483C>T	p.Cys161Cys	synonymous_variant	2/3		NP_001138738.1
SLC35C1	XM_011520203.4	c.522C>T	p.Cys174Cys	synonymous_variant	1/2		XP_011518505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC35C1	ENST00000314134.4	c.522C>T	p.Cys174Cys	synonymous_variant	1/2	1	NM_018389.5	ENSP00000313318.3
SLC35C1	ENST00000442528.2	c.483C>T	p.Cys161Cys	synonymous_variant	2/3	1		ENSP00000412408.2
SLC35C1	ENST00000526817.2	c.483C>T	p.Cys161Cys	synonymous_variant	2/3	2		ENSP00000432145.2
SLC35C1	ENST00000530471.1	c.483C>T	p.Cys161Cys	synonymous_variant	2/2	3		ENSP00000432669.1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00272 AC: 679 AN: 249702 Hom.: 3 AF XY: 0.00257 AC XY: 348 AN XY: 135208

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000687

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00267 AC: 3906 AN: 1460416 Hom.: 13 Cov.: 35 AF XY: 0.00259 AC XY: 1879 AN XY: 726524

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.00263

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00273 AC: 415 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74454

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.00162

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SLC35C1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Leukocyte adhesion deficiency type II Uncertain:1 Benign: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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.2
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs141379070; hg19: chr11-45827874; COSMIC: COSV58479447; COSMIC: COSV58479447;