rs145613857

chr11-45811294-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018389.5(SLC35C1):c.1054C>T(p.Pro352Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00504 in 1,556,504 control chromosomes in the GnomAD database, including 20 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P352H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (17 hom.)
• Consequence: SLC35C1 NM_018389.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.54

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004312724).
• BP6: Variant 11-45811294-C-T is Benign according to our data. Variant chr11-45811294-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252721.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr11-45811294-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00379 (578/152328) while in subpopulation NFE AF= 0.006 (408/68018). AF 95% confidence interval is 0.00552. There are 3 homozygotes in gnomad4. There are 254 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC35C1	NM_018389.5	c.1054C>T	p.Pro352Ser	missense_variant	2/2	ENST00000314134.4
SLC35C1	NM_001145265.2	c.1015C>T	p.Pro339Ser	missense_variant	3/3
SLC35C1	NM_001145266.1	c.1015C>T	p.Pro339Ser	missense_variant	3/3
SLC35C1	XM_011520202.3	c.547C>T	p.Pro183Ser	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC35C1	ENST00000314134.4	c.1054C>T	p.Pro352Ser	missense_variant	2/2	1	NM_018389.5	P4
SLC35C1	ENST00000442528.2	c.1015C>T	p.Pro339Ser	missense_variant	3/3	1		A1
SLC35C1	ENST00000526817.2	c.1015C>T	p.Pro339Ser	missense_variant	3/3	2		A1

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 578 AN: 152210 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00600

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00380 AC: 738 AN: 193980 Hom.: 0 AF XY: 0.00392 AC XY: 419 AN XY: 106764

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000266

Gnomad FIN exome AF: 0.00322

Gnomad NFE exome AF: 0.00578

Gnomad OTH exome AF: 0.00448

GnomAD4 exome AF: 0.00517 AC: 7262 AN: 1404176 Hom.: 17 Cov.: 36 AF XY: 0.00504 AC XY: 3502 AN XY: 694254

Gnomad4 AFR exome AF: 0.000724

Gnomad4 AMR exome AF: 0.00317

Gnomad4 ASJ exome AF: 0.00548

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000277

Gnomad4 FIN exome AF: 0.00289

Gnomad4 NFE exome AF: 0.00604

Gnomad4 OTH exome AF: 0.00466

GnomAD4 genome AF: 0.00379 AC: 578 AN: 152328 Hom.: 3 Cov.: 33 AF XY: 0.00341 AC XY: 254 AN XY: 74496

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.00600

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00444 Hom.: 3

Bravo AF: 0.00364

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00421 AC: 36

ExAC AF: 0.00365 AC: 441

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SLC35C1: BP4, BS2 -

Leukocyte adhesion deficiency type II Uncertain:1 Benign: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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 16, 2015

- -

SLC35C1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	18
Dann	Benign	0.93
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.95	N;N
REVEL	Benign	0.057
Sift	Benign	0.50	T;T
Sift4G	Benign	0.80	T;T
Polyphen		0.0050	.;B
Vest4		0.15
MVP		0.74
MPC		0.55
ClinPred		0.0023	T
GERP RS		4.8
Varity_R		0.063
gMVP		0.53

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: rs145613857; hg19: chr11-45832845;