chrX-48904951-C-G

Variant names:

• chrX-48904951-C-G
• rs140079332
• NM_005660.3:c.958G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005660.3(SLC35A2):​c.958G>C​(p.Val320Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,382 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V320M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SLC35A2 NM_005660.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 0 publications found

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]

SLC35A2 Gene-Disease associations (from GenCC):

• SLC35A2-congenital disorder of glycosylation

  Inheritance: XL, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.076236695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC35A2	NM_005660.3	c.958G>C	p.Val320Leu	missense_variant	Exon 4 of 5	ENST00000247138.11	NP_005651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC35A2	ENST00000247138.11	c.958G>C	p.Val320Leu	missense_variant	Exon 4 of 5	1	NM_005660.3	ENSP00000247138.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097382 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362762

African (AFR) AF: 0.00 AC: 0 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35143

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30191

South Asian (SAS) AF: 0.00 AC: 0 AN: 53998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841594

Other (OTH) AF: 0.00 AC: 0 AN: 46063

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.84
DEOGEN2	Benign	0.25	T;.;.;T;.
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.076	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.015	N;N;.;.;.
PhyloP100		1.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.53	N;N;.;.;N
REVEL	Benign	0.047
Sift	Benign	1.0	T;T;.;.;T
Sift4G	Benign	0.79	T;T;T;T;T
Polyphen		0.0030	B;B;.;B;.
Vest4		0.20
MutPred		0.69		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;.;
MVP		0.15
MPC		0.88
ClinPred		0.050	T
GERP RS		3.0
Varity_R		0.077
gMVP		0.78
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs140079332; hg19: chrX-48762228; COSMIC: COSV99504688; COSMIC: COSV99504688;