chrX-48904779-C-A

Variant names:

• chrX-48904779-C-A
• rs369048466
• NM_005660.3:c.1130G>T

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.1130G>T​(p.Arg377Leu) 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 1,097,750 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. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R377P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SLC35A2 NM_005660.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.761
• 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: Ambry Genetics, G2P, Orphanet, Illumina, PanelApp Australia, 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=0.0761663).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005660.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35A2	NM_005660.3	MANE Select	c.1130G>T	p.Arg377Leu	missense	Exon 4 of 5	NP_005651.1	P78381-1
	SLC35A2	NM_001282651.2		c.1214G>T	p.Arg405Leu	missense	Exon 5 of 5	NP_001269580.1	P78381-4
	SLC35A2	NM_001282650.2		c.1169G>T	p.Arg390Leu	missense	Exon 4 of 4	NP_001269579.1	B4DE15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35A2	ENST00000247138.11	TSL:1 MANE Select	c.1130G>T	p.Arg377Leu	missense	Exon 4 of 5	ENSP00000247138.5	P78381-1
	SLC35A2	ENST00000376521.6	TSL:1	c.1130G>T	p.Arg377Leu	missense	Exon 4 of 4	ENSP00000365704.1	P78381-2
	SLC35A2	ENST00000445167.7	TSL:1	c.540G>T	p.Pro180Pro	synonymous	Exon 4 of 4	ENSP00000402726.2	P78381-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097750 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363124

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19361

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841872

Other (OTH) AF: 0.00 AC: 0 AN: 46089

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Benign	0.078	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.76
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.071
Sift	Benign	0.13	T
Sift4G	Benign	0.92	T
Polyphen		0.032	B
Vest4		0.27
MutPred		0.16		Gain of helix (P = 0.0425)
MVP		0.043
MPC		1.1
ClinPred		0.033	T
GERP RS		0.47
Varity_R		0.077
gMVP		0.36
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs369048466; hg19: chrX-48762056;