chr6-44254765-G-A

Variant names:

• chr6-44254765-G-A
• rs200968592
• NM_178148.4:c.1240C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_178148.4(SLC35B2):​c.1240C>T​(p.Arg414Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R414H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SLC35B2 NM_178148.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30
• Publications: 1 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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

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.1240C>T	p.Arg414Cys	missense	Exon 4 of 4	NP_835361.1	Q8TB61-1
	SLC35B2	NM_001286509.2		c.1225C>T	p.Arg409Cys	missense	Exon 4 of 4	NP_001273438.1
	SLC35B2	NM_001286510.2		c.1225C>T	p.Arg409Cys	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.1240C>T	p.Arg414Cys	missense	Exon 4 of 4	ENSP00000377401.3	Q8TB61-1
	SLC35B2	ENST00000615337.4	TSL:4	c.1093C>T	p.Arg365Cys	missense	Exon 4 of 4	ENSP00000480681.1	Q8TB61-3
	SLC35B2	ENST00000538577.5	TSL:2	c.961C>T	p.Arg321Cys	missense	Exon 3 of 3	ENSP00000443845.1	Q8TB61-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251194 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461854 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000235 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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	0.22
BayesDel_addAF	Benign	-0.0095	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.68		Loss of disorder (P = 0.0082)
MVP		0.24
MPC		0.67
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.73
Mutation Taster		=52/48	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: rs200968592; hg19: chr6-44222502;