rs139066012

Positions:

• chr10-71362126-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018344.6(SLC29A3):​c.946T>G​(p.Phe316Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,614,098 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: SLC29A3 NM_018344.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.84

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058559716).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC29A3	NM_018344.6	c.946T>G	p.Phe316Val	missense_variant	6/6	ENST00000373189.6	NP_060814.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC29A3	ENST00000373189.6	c.946T>G	p.Phe316Val	missense_variant	6/6	1	NM_018344.6	ENSP00000362285.5

Frequencies

GnomAD3 genomes AF: 0.000776 AC: 118 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000780 AC: 196 AN: 251408 Hom.: 1 AF XY: 0.000729 AC XY: 99 AN XY: 135878

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00119 AC: 1744 AN: 1461858 Hom.: 2 Cov.: 34 AF XY: 0.00111 AC XY: 806 AN XY: 727220

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00142

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74432

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.000824

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000749 AC: 91

EpiCase AF: 0.00131

EpiControl AF: 0.00172

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

H syndrome Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 316 of the SLC29A3 protein (p.Phe316Val). This variant is present in population databases (rs139066012, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. 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: 300367). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC29A3 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	SLC29A3 NM_018344.5 exon 6 p.Phe316Val (c.946T>G): This variant has not been reported in the literature but is present in 0.1% (159/129102) of European alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/10-73121883-T-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:300367). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T;T;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.74	.;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.3	M;M;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.6	.;D;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.53
MVP		0.71
MPC		0.36
ClinPred		0.14	T
GERP RS		2.0
Varity_R		0.81
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs139066012; hg19: chr10-73121883;