rs2252996

chr10-71356185-G-Achr10-71356185-G-Cchr10-71356185-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018344.6(SLC29A3):c.715G>A(p.Val239Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.864 in 1,613,592 control chromosomes in the GnomAD database, including 606,088 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V239V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.84 (54379 hom., cov: 32)
  • Exomes 𝑓: 0.87 (551709 hom.)
• Consequence: SLC29A3 NM_018344.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.160

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.0462653E-7).
• BP6: Variant 10-71356185-G-A is Benign according to our data. Variant chr10-71356185-G-A is described in ClinVar as [Benign]. Clinvar id is 130344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71356185-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC29A3	NM_018344.6	c.715G>A	p.Val239Ile	missense_variant	5/6	ENST00000373189.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC29A3	ENST00000373189.6	c.715G>A	p.Val239Ile	missense_variant	5/6	1	NM_018344.6	P1

Frequencies

GnomAD3 genomes AF: 0.843 AC: 127916 AN: 151700 Hom.: 54373 Cov.: 32

Gnomad AFR AF: 0.814

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.938

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.767

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.889

Gnomad OTH AF: 0.865

GnomAD3 exomes AF: 0.818 AC: 205690 AN: 251338 Hom.: 85517 AF XY: 0.826 AC XY: 112261 AN XY: 135840

Gnomad AFR exome AF: 0.811

Gnomad AMR exome AF: 0.642

Gnomad ASJ exome AF: 0.937

Gnomad EAS exome AF: 0.687

Gnomad SAS exome AF: 0.774

Gnomad FIN exome AF: 0.864

Gnomad NFE exome AF: 0.885

Gnomad OTH exome AF: 0.857

GnomAD4 exome AF: 0.866 AC: 1266087 AN: 1461776 Hom.: 551709 Cov.: 64 AF XY: 0.865 AC XY: 629144 AN XY: 727188

Gnomad4 AFR exome AF: 0.818

Gnomad4 AMR exome AF: 0.648

Gnomad4 ASJ exome AF: 0.935

Gnomad4 EAS exome AF: 0.652

Gnomad4 SAS exome AF: 0.781

Gnomad4 FIN exome AF: 0.865

Gnomad4 NFE exome AF: 0.889

Gnomad4 OTH exome AF: 0.867

GnomAD4 genome AF: 0.843 AC: 127968 AN: 151816 Hom.: 54379 Cov.: 32 AF XY: 0.840 AC XY: 62294 AN XY: 74180

Gnomad4 AFR AF: 0.814

Gnomad4 AMR AF: 0.749

Gnomad4 ASJ AF: 0.938

Gnomad4 EAS AF: 0.677

Gnomad4 SAS AF: 0.766

Gnomad4 FIN AF: 0.866

Gnomad4 NFE AF: 0.889

Gnomad4 OTH AF: 0.861

Alfa AF: 0.878 Hom.: 148210

Bravo AF: 0.832

TwinsUK AF: 0.882 AC: 3269

ALSPAC AF: 0.883 AC: 3404

ESP6500AA AF: 0.809 AC: 3563

ESP6500EA AF: 0.889 AC: 7643

ExAC AF: 0.822 AC: 99742

Asia WGS AF: 0.694 AC: 2416 AN: 3478

EpiCase AF: 0.896

EpiControl AF: 0.897

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

H syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Apr 27, 2023	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 94% of patients studied by a panel of primary immunodeficiencies. Number of patients: 90. Only high quality variants are reported. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.0080
Dann	Benign	0.74
DEOGEN2	Benign	0.011	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.058	N
MetaRNN	Benign	7.0e-7	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
Polyphen		0.0020	B;B;.
Vest4		0.049
MPC		0.061
ClinPred		0.0077	T
GERP RS		-2.2
Varity_R		0.0098
gMVP		0.15

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: rs2252996; hg19: chr10-73115942; COSMIC: COSV104427495;