Genetic Variant NM_001370476.2:c.871A>G (chr6-8417404-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001370476.2(SLC35B3):c.871A>G(p.Lys291Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,424,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC35B3
NM_001370476.2 missense, splice_region

Scores

Splicing: ADA: 0.002422

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.666

Publications

0 publications found

Variant links:

Genes affected

SLC35B3 (HGNC:21601): (solute carrier family 35 member B3) This gene is a member of the solute carrier family. The encoded protein is involved in the transport of 3-prime phosphoadenosine 5-prime phosphosulfate (PAPS) from the nucleus or the cytosol to the Golgi lumen. This gene has been reported to be expressed preferentially in the human colon tissues. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

SLC35B3 links:

ENSG00000285216 (HGNC:):

ENSG00000285216 links:

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ACMG classification

Classification was made for transcript

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=0.1106357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC35B3	NM_001370476.2 link	c.871A>G	p.Lys291Glu	missense_variant, splice_region_variant	Exon 8 of 11	ENST00000644923.2	NP_001357405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC35B3	ENST00000644923.2 link	c.871A>G	p.Lys291Glu	missense_variant, splice_region_variant	Exon 8 of 11		NM_001370476.2	ENSP00000496368.1		Q9H1N7-1
SLC35B3	ENST00000710437.1 link	c.775A>G	p.Lys259Glu	missense_variant, splice_region_variant	Exon 7 of 10			ENSP00000518269.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1424808

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709706

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31676

American (AMR)

AF:

0.00

AC:

AN:

38388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25438

East Asian (EAS)

AF:

0.00

AC:

AN:

39260

South Asian (SAS)

AF:

0.00

AC:

AN:

81036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5572

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1091292

Other (OTH)

AF:

0.00

AC:

AN:

58998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 29, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.871A>G (p.K291E) alteration is located in exon 8 (coding exon 7) of the SLC35B3 gene. This alteration results from a A to G substitution at nucleotide position 871, causing the lysine (K) at amino acid position 291 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.015

.;T;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.022

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.82

T;.;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

.;N;N

PhyloP100

0.67

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.44

.;N;.

REVEL

Benign

0.037

Sift

Benign

0.60

.;T;.

Sift4G

Benign

0.92

.;T;.

Polyphen

0.0010

.;B;B

Vest4

0.27

MutPred

0.62

.;Loss of ubiquitination at K291 (P = 0.0155);Loss of ubiquitination at K291 (P = 0.0155);

MVP

0.12

MPC

0.14

ClinPred

0.28

GERP RS

4.5

Varity_R

0.085

gMVP

0.52

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0024

dbscSNV1_RF

Benign

0.082

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.40

Position offset: -2

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

Publications

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NM_001370476.2:c.871A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over