rs55719932

Variant names:

• chrX-48911594-G-T
• rs55719932
• NM_005660.3:c.43C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005660.3(SLC35A2):​c.43C>A​(p.Pro15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,163,770 control chromosomes in the GnomAD database, including 226 homozygotes. There are 8,200 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (16 hom., 532 hem., cov: 25)
  • Exomes 𝑓: 0.023 (210 hom. 7668 hem.)
• Consequence: SLC35A2 NM_005660.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.345
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017829537).
• BP6: Variant X-48911594-G-T is Benign according to our data. Variant chrX-48911594-G-T is described in ClinVar as Benign. ClinVar VariationId is 380583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0154 (1741/113251) while in subpopulation NFE AF = 0.0238 (1268/53268). AF 95% confidence interval is 0.0227. There are 16 homozygotes in GnomAd4. There are 532 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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.43C>A	p.Pro15Thr	missense	Exon 1 of 5	NP_005651.1	P78381-1
	SLC35A2	NM_001282651.2		c.43C>A	p.Pro15Thr	missense	Exon 1 of 5	NP_001269580.1	P78381-4
	SLC35A2	NM_001282650.2		c.43C>A	p.Pro15Thr	missense	Exon 1 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.43C>A	p.Pro15Thr	missense	Exon 1 of 5	ENSP00000247138.5	P78381-1
	SLC35A2	ENST00000376521.6	TSL:1	c.43C>A	p.Pro15Thr	missense	Exon 1 of 4	ENSP00000365704.1	P78381-2
	SLC35A2	ENST00000445167.7	TSL:1	c.43C>A	p.Pro15Thr	missense	Exon 1 of 4	ENSP00000402726.2	P78381-3

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 1740 AN: 113199 Hom.: 16 Cov.: 25

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.00733

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00942

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00708

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0176

GnomAD2 exomes AF: 0.0161 AC: 1732 AN: 107447 AF XY: 0.0153

Gnomad AFR exome AF: 0.00410

Gnomad AMR exome AF: 0.00800

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0310

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0231 AC: 24234 AN: 1050519 Hom.: 210 Cov.: 31 AF XY: 0.0224 AC XY: 7668 AN XY: 342897

African (AFR) AF: 0.00260 AC: 65 AN: 25015

American (AMR) AF: 0.00806 AC: 233 AN: 28924

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 221 AN: 18655

East Asian (EAS) AF: 0.0000730 AC: 2 AN: 27409

South Asian (SAS) AF: 0.00715 AC: 358 AN: 50065

European-Finnish (FIN) AF: 0.0283 AC: 877 AN: 30984

Middle Eastern (MID) AF: 0.0138 AC: 49 AN: 3540

European-Non Finnish (NFE) AF: 0.0261 AC: 21448 AN: 821541

Other (OTH) AF: 0.0221 AC: 981 AN: 44386

GnomAD4 genome AF: 0.0154 AC: 1741 AN: 113251 Hom.: 16 Cov.: 25 AF XY: 0.0150 AC XY: 532 AN XY: 35409

African (AFR) AF: 0.00374 AC: 117 AN: 31319

American (AMR) AF: 0.0102 AC: 111 AN: 10848

Ashkenazi Jewish (ASJ) AF: 0.00942 AC: 25 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00746 AC: 21 AN: 2814

European-Finnish (FIN) AF: 0.0258 AC: 163 AN: 6316

Middle Eastern (MID) AF: 0.0183 AC: 4 AN: 219

European-Non Finnish (NFE) AF: 0.0238 AC: 1268 AN: 53268

Other (OTH) AF: 0.0174 AC: 27 AN: 1554

Alfa AF: 0.0191 Hom.: 144

Bravo AF: 0.0136

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0239 AC: 69

ESP6500AA AF: 0.00172 AC: 6

ESP6500EA AF: 0.0212 AC: 130

ExAC AF: 0.0126 AC: 1245

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	4.8
DANN	Benign	0.93
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.34
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.023
Sift	Benign	0.033	D
Sift4G	Benign	0.23	T
Polyphen		0.22	B
Vest4		0.14
MPC		1.0
ClinPred		0.0011	T
GERP RS		2.1
PromoterAI		-0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.33
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55719932; hg19: chrX-48768871; COSMIC: COSV55946578; COSMIC: COSV55946578;