rs780668

Positions:

• chr10-71351651-C-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.473C>T​(p.Ser158Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.701 in 1,613,958 control chromosomes in the GnomAD database, including 409,244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,drug response (★★). Synonymous variant affecting the same amino acid position (i.e. S158S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.61 (31114 hom., cov: 32)
  • Exomes 𝑓: 0.71 (378130 hom.)
• Consequence: SLC29A3 NM_018344.6 missense
• Clinical Significance: Benign; drug response criteria provided, multiple submitters, no conflicts B:7 O:3
• Conservation: PhyloP100: 7.50

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=3.6845643E-6).
• BP6: Variant 10-71351651-C-T is Benign according to our data. Variant chr10-71351651-C-T is described in ClinVar as [Benign, drug_response]. Clinvar id is 130341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71351651-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC29A3	NM_018344.6	c.473C>T	p.Ser158Phe	missense_variant	4/6	ENST00000373189.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC29A3	ENST00000373189.6	c.473C>T	p.Ser158Phe	missense_variant	4/6	1	NM_018344.6	P1

Frequencies

GnomAD3 genomes AF: 0.613 AC: 93188 AN: 151976 Hom.: 31124 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.741

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.760

Gnomad OTH AF: 0.645

GnomAD3 exomes AF: 0.639 AC: 160758 AN: 251472 Hom.: 54270 AF XY: 0.650 AC XY: 88296 AN XY: 135908

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.485

Gnomad ASJ exome AF: 0.733

Gnomad EAS exome AF: 0.456

Gnomad SAS exome AF: 0.530

Gnomad FIN exome AF: 0.741

Gnomad NFE exome AF: 0.755

Gnomad OTH exome AF: 0.697

GnomAD4 exome AF: 0.711 AC: 1038771 AN: 1461864 Hom.: 378130 Cov.: 63 AF XY: 0.708 AC XY: 514870 AN XY: 727236

Gnomad4 AFR exome AF: 0.356

Gnomad4 AMR exome AF: 0.492

Gnomad4 ASJ exome AF: 0.734

Gnomad4 EAS exome AF: 0.364

Gnomad4 SAS exome AF: 0.539

Gnomad4 FIN exome AF: 0.744

Gnomad4 NFE exome AF: 0.755

Gnomad4 OTH exome AF: 0.689

GnomAD4 genome AF: 0.613 AC: 93189 AN: 152094 Hom.: 31114 Cov.: 32 AF XY: 0.610 AC XY: 45321 AN XY: 74356

Gnomad4 AFR AF: 0.362

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.736

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.741

Gnomad4 NFE AF: 0.760

Gnomad4 OTH AF: 0.643

Alfa AF: 0.717 Hom.: 83919

Bravo AF: 0.588

TwinsUK AF: 0.746 AC: 2766

ALSPAC AF: 0.752 AC: 2900

ESP6500AA AF: 0.367 AC: 1615

ESP6500EA AF: 0.747 AC: 6426

ExAC AF: 0.638 AC: 77492

Asia WGS AF: 0.460 AC: 1602 AN: 3478

EpiCase AF: 0.756

EpiControl AF: 0.759

ClinVar

Significance: Benign; drug response

Submissions summary: Benign:7 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 83. 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2018	- -

H syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 28842327) -

Gemcitabine response Other:1

drug response, criteria provided, single submitter

research

Bioinformatics Institute, Agency for Science, Technology and Research

Jan 01, 2017

- correlated with patient outcome with gemcitabine-based chemotherpy

Acanthosis nigricans Other:1

association, no assertion criteria provided

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in this gene can predispose to acanthosis nigricans in patients with insulin dependent diabetes. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	1.0	D
MetaRNN	Benign	0.0000037	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.1	M;M;.
MutationTaster	Benign	6.1e-10	P
PrimateAI	Uncertain	0.54	T
Polyphen		0.66	P;P;.
Vest4		0.31
MPC		0.39
ClinPred		0.064	T
GERP RS		4.6
Varity_R		0.30
gMVP		0.61

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: rs780668; hg19: chr10-73111408; COSMIC: COSV64385485; COSMIC: COSV64385485;