X-48904779-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005660.3(SLC35A2):c.1130G>A(p.Arg377His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000364 in 1,209,745 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000039 (0 hom. 8 hem.)
• Consequence: SLC35A2 NM_005660.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.761

Genes affected

SLC35A2 (HGNC:11022): (solute carrier family 35 member A2) This gene encodes a member of the nucleotide-sugar transporter family. The encoded protein is a multi-pass membrane protein. It transports UDP-galactose from the cytosol into Golgi vesicles, where it serves as a glycosyl donor for the generation of glycans. Mutations in this gene cause congenital disorder of glycosylation type IIm (CDG2M). Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035562873).
• BP6: Variant X-48904779-C-T is Benign according to our data. Variant chrX-48904779-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 701360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC35A2	NM_005660.3	c.1130G>A	p.Arg377His	missense_variant	4/5	ENST00000247138.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC35A2	ENST00000247138.11	c.1130G>A	p.Arg377His	missense_variant	4/5	1	NM_005660.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111995 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34163

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000666

GnomAD3 exomes AF: 0.0000219 AC: 4 AN: 182268 Hom.: 0 AF XY: 0.0000449 AC XY: 3 AN XY: 66850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000529

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000392 AC: 43 AN: 1097750 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 8 AN XY: 363124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000199

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000404

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111995 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34163

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000666

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SLC35A2-congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	12
Dann	Benign	0.90
DEOGEN2	Benign	0.15	T;.;.;T;.
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.036	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;.;.;.
MutationTaster	Benign	0.84	D;D;D;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.15	N;N;.;.;N
REVEL	Benign	0.053
Sift	Benign	0.28	T;T;.;.;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.0	B;B;.;B;.
Vest4		0.029
MutPred		0.13		Loss of stability (P = 0.0982);Loss of stability (P = 0.0982);.;.;.;
MVP		0.068
MPC		1.1
ClinPred		0.026	T
GERP RS		0.47
Varity_R		0.036
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs369048466; hg19: chrX-48762056;