rs558547846

Positions:

chr10-71322776-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018344.6(SLC29A3):c.22G>A(p.Asp8Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,998 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 1 hom. )

Consequence

SLC29A3
NM_018344.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.356

Variant links:

Genes affected

SLC29A3 (HGNC:23096): (solute carrier family 29 member 3) This gene encodes a nucleoside transporter. The encoded protein plays a role in cellular uptake of nucleosides, nucleobases, and their related analogs. Mutations in this gene have been associated with H syndrome, which is characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, and hypogonadism. A related disorder, PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus), has also been associated with mutations at this locus. Alternatively spliced transcript variants have been described.[provided by RefSeq, Mar 2010]

SLC29A3 links:

SLC29A3 (HGNC:):

SLC29A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.033686787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC29A3	NM_018344.6 linkuse as main transcript	c.22G>A	p.Asp8Asn	missense_variant	2/6	ENST00000373189.6	NP_060814.4	Q9BZD2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC29A3	ENST00000373189.6 linkuse as main transcript	c.22G>A	p.Asp8Asn	missense_variant	2/6	1	NM_018344.6	ENSP00000362285.5		Q9BZD2-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000602

AC:

AN:

249018

Hom.:

AF XY:

0.0000593

AC XY:

AN XY:

134814

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000126

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000924

AC:

135

AN:

1461814

Hom.:

Cov.:

AF XY:

0.0000866

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000118

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000147

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.22G>A (p.D8N) alteration is located in exon 2 (coding exon 2) of the SLC29A3 gene. This alteration results from a G to A substitution at nucleotide position 22, causing the aspartic acid (D) at amino acid position 8 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

H syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 13, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 8 of the SLC29A3 protein (p.Asp8Asn). This variant is present in population databases (rs558547846, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SLC29A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 581253). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.6

DANN

Benign

0.48

DEOGEN2

Benign

0.017

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.49

.;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.32

.;N

REVEL

Benign

0.035

Sift

Benign

0.45

.;T

Polyphen

0.0

B;B

Vest4

0.066

MVP

0.46

MPC

0.059

ClinPred

0.015

GERP RS

-2.4

Varity_R

0.028

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over