rs146971634

Positions:

• chr11-45810838-G-A

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.598G>A​(p.Val200Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,612,388 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: SLC35C1 NM_018389.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.59

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=0.005933225).
• BP6: Variant 11-45810838-G-A is Benign according to our data. Variant chr11-45810838-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 530701.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00108 (164/152352) while in subpopulation AFR AF= 0.00356 (148/41580). AF 95% confidence interval is 0.00309. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC35C1	NM_018389.5	c.598G>A	p.Val200Ile	missense_variant	2/2	ENST00000314134.4
SLC35C1	NM_001145265.2	c.559G>A	p.Val187Ile	missense_variant	3/3
SLC35C1	NM_001145266.1	c.559G>A	p.Val187Ile	missense_variant	3/3
SLC35C1	XM_011520202.3	c.91G>A	p.Val31Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC35C1	ENST00000314134.4	c.598G>A	p.Val200Ile	missense_variant	2/2	1	NM_018389.5	P4
SLC35C1	ENST00000442528.2	c.559G>A	p.Val187Ile	missense_variant	3/3	1		A1
SLC35C1	ENST00000526817.2	c.559G>A	p.Val187Ile	missense_variant	3/3	2		A1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000277 AC: 69 AN: 248750 Hom.: 1 AF XY: 0.000222 AC XY: 30 AN XY: 134926

Gnomad AFR exome AF: 0.00356

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000127 AC: 186 AN: 1460036 Hom.: 2 Cov.: 37 AF XY: 0.000105 AC XY: 76 AN XY: 726456

Gnomad4 AFR exome AF: 0.00373

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.00110 AC XY: 82 AN XY: 74496

Gnomad4 AFR AF: 0.00356

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000211 Hom.: 0

Bravo AF: 0.00126

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.598G>A (p.V200I) alteration is located in exon 2 (coding exon 2) of the SLC35C1 gene. This alteration results from a G to A substitution at nucleotide position 598, causing the valine (V) at amino acid position 200 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Leukocyte adhesion deficiency type II Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The SLC35C1 p.Val187Ile variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs146971634) and ClinVar (classified as likely benign). The variant was also identified in control databases in 107 of 280140 chromosomes (1 homozygous) at a frequency of 0.000382 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 94 of 24732 chromosomes (freq: 0.003801), Other in 3 of 7176 chromosomes (freq: 0.000418), Latino in 7 of 35384 chromosomes (freq: 0.000198), South Asian in 1 of 30614 chromosomes (freq: 0.000033) and European (non-Finnish) in 2 of 128374 chromosomes (freq: 0.000016), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Val187 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.0080
DANN	Benign	0.78
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.47	N;N
REVEL	Benign	0.036
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.038
MVP		0.36
MPC		0.44
ClinPred		0.0019	T
GERP RS		-2.7
Varity_R		0.021
gMVP		0.10

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: rs146971634; hg19: chr11-45832389;