Genetic Variant SLC35B3:p.Val229Leu (chr6-8419675-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001370476.2(SLC35B3):c.685G>T(p.Val229Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,345,380 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V229M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

SLC35B3
NM_001370476.2 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.69

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC35B3	NM_001370476.2 link	c.685G>T	p.Val229Leu	missense_variant, splice_region_variant	Exon 7 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.685G>T	p.Val229Leu	missense_variant, splice_region_variant	Exon 7 of 11		NM_001370476.2	ENSP00000496368.1		Q9H1N7-1
SLC35B3	ENST00000710437.1 link	c.589G>T	p.Val197Leu	missense_variant, splice_region_variant	Exon 6 of 10			ENSP00000518269.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.43e-7

AC:

AN:

1345380

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

665664

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30008

American (AMR)

AF:

0.00

AC:

AN:

35356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23328

East Asian (EAS)

AF:

0.00

AC:

AN:

36558

South Asian (SAS)

AF:

0.0000145

AC:

AN:

69048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5338

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1041278

Other (OTH)

AF:

0.00

AC:

AN:

54620

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.060

.;T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.61

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;L;L

PhyloP100

7.7

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.2

.;N;.

REVEL

Benign

0.20

Sift

Uncertain

0.012

.;D;.

Sift4G

Uncertain

0.027

.;D;.

Polyphen

0.30

.;B;B

Vest4

0.78

MutPred

0.55

.;Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);

MVP

0.39

MPC

0.31

ClinPred

0.97

GERP RS

5.4

Varity_R

0.45

gMVP

0.62

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over