rs1060503677

Variant names:

• chrX-48909809-C-T
• rs1060503677
• NM_005660.3:c.274+5G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PP3_Strong BP6 BS2

The NM_005660.3(SLC35A2):​c.274+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,201,328 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000017 (0 hom. 6 hem.)
• Consequence: SLC35A2 NM_005660.3 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.60
• 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: Likely_benign. The variant received -1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant X-48909809-C-T is Benign according to our data. Variant chrX-48909809-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 412238.
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL,Unknown gene

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.274+5G>A		splice_region intron	N/A	NP_005651.1	P78381-1
	SLC35A2	NM_001282651.2		c.358+5G>A		splice_region intron	N/A	NP_001269580.1	P78381-4
	SLC35A2	NM_001282650.2		c.313+5G>A		splice_region intron	N/A	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.274+5G>A		splice_region intron	N/A	ENSP00000247138.5	P78381-1
	SLC35A2	ENST00000376521.6	TSL:1	c.274+5G>A		splice_region intron	N/A	ENSP00000365704.1	P78381-2
	SLC35A2	ENST00000445167.7	TSL:1	c.274+5G>A		splice_region intron	N/A	ENSP00000402726.2	P78381-3

Frequencies

GnomAD3 genomes AF: 0.00000885 AC: 1 AN: 113035 Hom.: 0 Cov.: 24

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: 0.0000187

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000181 AC: 3 AN: 166125 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000769

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000175 AC: 19 AN: 1088293 Hom.: 0 Cov.: 30 AF XY: 0.0000169 AC XY: 6 AN XY: 355065

African (AFR) AF: 0.00 AC: 0 AN: 26230

American (AMR) AF: 0.000116 AC: 4 AN: 34480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19147

East Asian (EAS) AF: 0.00 AC: 0 AN: 29909

South Asian (SAS) AF: 0.000171 AC: 9 AN: 52773

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4102

European-Non Finnish (NFE) AF: 0.00000718 AC: 6 AN: 835812

Other (OTH) AF: 0.00 AC: 0 AN: 45718

GnomAD4 genome AF: 0.00000885 AC: 1 AN: 113035 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 35173

African (AFR) AF: 0.00 AC: 0 AN: 31141

American (AMR) AF: 0.00 AC: 0 AN: 10790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2662

East Asian (EAS) AF: 0.00 AC: 0 AN: 3596

South Asian (SAS) AF: 0.00 AC: 0 AN: 2801

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53335

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Pathogenic	29
DANN	Benign	0.77
PhyloP100		1.6
PromoterAI		-0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.58		Position offset: 44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060503677; hg19: chrX-48767086;