rs780668

Variant names:

• chr10-71351651-C-T
• rs780668
• NM_018344.6:c.473C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 57 publications found

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 Gene-Disease associations (from GenCC):

• H syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• dysosteosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 130341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SLC29A3	NM_018344.6	c.473C>T	p.Ser158Phe	missense_variant	Exon 4 of 6	ENST00000373189.6	NP_060814.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC29A3	ENST00000373189.6	c.473C>T	p.Ser158Phe	missense_variant	Exon 4 of 6	1	NM_018344.6	ENSP00000362285.5

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

GnomAD2 exomes AF: 0.639 AC: 160758 AN: 251472 AF XY: 0.650

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 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

African (AFR) AF: 0.356 AC: 11914 AN: 33480

American (AMR) AF: 0.492 AC: 21998 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 19174 AN: 26136

East Asian (EAS) AF: 0.364 AC: 14468 AN: 39700

South Asian (SAS) AF: 0.539 AC: 46495 AN: 86256

European-Finnish (FIN) AF: 0.744 AC: 39722 AN: 53418

Middle Eastern (MID) AF: 0.714 AC: 4117 AN: 5768

European-Non Finnish (NFE) AF: 0.755 AC: 839266 AN: 1111986

Other (OTH) AF: 0.689 AC: 41617 AN: 60396

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

African (AFR) AF: 0.362 AC: 15001 AN: 41458

American (AMR) AF: 0.586 AC: 8955 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2556 AN: 3472

East Asian (EAS) AF: 0.428 AC: 2210 AN: 5162

South Asian (SAS) AF: 0.523 AC: 2515 AN: 4810

European-Finnish (FIN) AF: 0.741 AC: 7858 AN: 10606

Middle Eastern (MID) AF: 0.685 AC: 200 AN: 292

European-Non Finnish (NFE) AF: 0.760 AC: 51693 AN: 67998

Other (OTH) AF: 0.643 AC: 1359 AN: 2114

Alfa AF: 0.703 Hom.: 156226

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

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 11, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

H syndrome Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28842327) -

Gemcitabine response Other:1

Jan 01, 2017

Bioinformatics Institute, Agency for Science, Technology and Research

Significance: drug response

Review Status: criteria provided, single submitter

Collection Method: research

- correlated with patient outcome with gemcitabine-based chemotherpy

Acanthosis nigricans Other:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: association

Review Status: no assertion criteria provided

Collection Method: research

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
LIST_S2	Uncertain	0.92	.;D;D
MetaRNN	Benign	0.0000037	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.1	M;M;.
PhyloP100		7.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.3	.;D;.
REVEL	Benign	0.29
Sift	Benign	0.062	.;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

Other links and lift over

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