X-48905091-C-G

Variant names:

• chrX-48905091-C-G
• rs1557042798
• NM_005660.3:c.818G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_005660.3(SLC35A2):​c.818G>C​(p.Gly273Ala) 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 1,097,570 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. 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. G273D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SLC35A2 NM_005660.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.89
• 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 1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_005660.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21423656).
• BP6: Variant X-48905091-C-G is Benign according to our data. Variant chrX-48905091-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 810587.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35A2	NM_005660.3	MANE Select	c.818G>C	p.Gly273Ala	missense	Exon 4 of 5	NP_005651.1
	SLC35A2	NM_001282651.2		c.902G>C	p.Gly301Ala	missense	Exon 5 of 5	NP_001269580.1
	SLC35A2	NM_001282650.2		c.857G>C	p.Gly286Ala	missense	Exon 4 of 4	NP_001269579.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35A2	ENST00000247138.11	TSL:1 MANE Select	c.818G>C	p.Gly273Ala	missense	Exon 4 of 5	ENSP00000247138.5
	SLC35A2	ENST00000376521.6	TSL:1	c.818G>C	p.Gly273Ala	missense	Exon 4 of 4	ENSP00000365704.1
	SLC35A2	ENST00000445167.7	TSL:1	c.427-199G>C		intron	N/A	ENSP00000402726.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000554 AC: 1 AN: 180437 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097570 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362950

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.00 AC: 0 AN: 35162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40463

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841770

Other (OTH) AF: 0.0000217 AC: 1 AN: 46065

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	SLC35A2-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.85
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.51	N
PhyloP100		1.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.048
Sift	Benign	0.51	T
Sift4G	Benign	0.52	T
Polyphen		0.0040	B
Vest4		0.33
MutPred		0.38		Loss of loop (P = 0.0804)
MVP		0.19
MPC		0.96
ClinPred		0.081	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.82
Mutation Taster		=30/70	disease causing

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: rs1557042798; hg19: chrX-48762368;