6-44254753-G-A

Variant names:

• chr6-44254753-G-A
• rs138499828
• NM_178148.4:c.1252C>T

Variant summary

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

The NM_178148.4(SLC35B2):​c.1252C>T​(p.Arg418Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: SLC35B2 NM_178148.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.737
• Publications: 3 publications found

Genes affected

SLC35B2 (HGNC:16872): (solute carrier family 35 member B2) Sulfotransferases (e.g., SULT4A1; MIM 608359) use an activated form of sulfate, 3-prime-phosphoadenosine 5-prime-phosphosulfate (PAPS), as a common sulfate donor for sulfation of glycoproteins, proteoglycans, and glycolipids in the endoplasmic reticulum and Golgi apparatus. SLC35B2 is located in the microsomal membrane and transports PAPS from the cytosol, where it is synthesized, into the Golgi lumen (Kamiyama et al., 2003 [PubMed 12716889]).[supplied by OMIM, Mar 2008]

SLC35B2 Gene-Disease associations (from GenCC):

• leukodystrophy, hypomyelinating, 26, with chondrodysplasia

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia

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=0.16761228).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178148.4. 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
	SLC35B2	NM_178148.4	MANE Select	c.1252C>T	p.Arg418Trp	missense	Exon 4 of 4	NP_835361.1	Q8TB61-1
	SLC35B2	NM_001286509.2		c.1237C>T	p.Arg413Trp	missense	Exon 4 of 4	NP_001273438.1
	SLC35B2	NM_001286510.2		c.1237C>T	p.Arg413Trp	missense	Exon 4 of 4	NP_001273439.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35B2	ENST00000393812.4	TSL:1 MANE Select	c.1252C>T	p.Arg418Trp	missense	Exon 4 of 4	ENSP00000377401.3	Q8TB61-1
	SLC35B2	ENST00000615337.4	TSL:4	c.1105C>T	p.Arg369Trp	missense	Exon 4 of 4	ENSP00000480681.1	Q8TB61-3
	SLC35B2	ENST00000538577.5	TSL:2	c.973C>T	p.Arg325Trp	missense	Exon 3 of 3	ENSP00000443845.1	Q8TB61-4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000638 AC: 16 AN: 250968 AF XY: 0.0000664

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1461728 Hom.: 0 Cov.: 30 AF XY: 0.0000743 AC XY: 54 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000179 AC: 8 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000971 AC: 108 AN: 1111886

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41518

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000629 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.74
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.11
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.58
MVP		0.082
MPC		0.52
ClinPred		0.21	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.60
Mutation Taster		=88/12	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: rs138499828; hg19: chr6-44222490; COSMIC: COSV51490545; COSMIC: COSV51490545;