10-71362188-T-C

Variant names:

• chr10-71362188-T-C
• rs1084004
• NM_018344.6:c.1008T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018344.6(SLC29A3):​c.1008T>C​(p.Gly336Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,613,930 control chromosomes in the GnomAD database, including 633,326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54089 hom., cov: 31)
  • Exomes 𝑓: 0.89 (579237 hom.)
• Consequence: SLC29A3 NM_018344.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.338
• Publications: 30 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-71362188-T-C is Benign according to our data. Variant chr10-71362188-T-C is described in ClinVar as Benign. ClinVar VariationId is 130337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.338 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC29A3	NM_018344.6	c.1008T>C	p.Gly336Gly	synonymous_variant	Exon 6 of 6	ENST00000373189.6	NP_060814.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC29A3	ENST00000373189.6	c.1008T>C	p.Gly336Gly	synonymous_variant	Exon 6 of 6	1	NM_018344.6	ENSP00000362285.5

Frequencies

GnomAD3 genomes AF: 0.839 AC: 127430 AN: 151934 Hom.: 54069 Cov.: 31

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.748

Gnomad ASJ AF: 0.945

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.837

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.916

Gnomad OTH AF: 0.856

GnomAD2 exomes AF: 0.825 AC: 207364 AN: 251278 AF XY: 0.835

Gnomad AFR exome AF: 0.754

Gnomad AMR exome AF: 0.626

Gnomad ASJ exome AF: 0.946

Gnomad EAS exome AF: 0.723

Gnomad FIN exome AF: 0.837

Gnomad NFE exome AF: 0.912

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.887 AC: 1296561 AN: 1461878 Hom.: 579237 Cov.: 82 AF XY: 0.886 AC XY: 644087 AN XY: 727238

African (AFR) AF: 0.749 AC: 25087 AN: 33480

American (AMR) AF: 0.633 AC: 28325 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.944 AC: 24661 AN: 26136

East Asian (EAS) AF: 0.715 AC: 28367 AN: 39700

South Asian (SAS) AF: 0.779 AC: 67179 AN: 86258

European-Finnish (FIN) AF: 0.844 AC: 45062 AN: 53414

Middle Eastern (MID) AF: 0.920 AC: 5304 AN: 5768

European-Non Finnish (NFE) AF: 0.917 AC: 1019314 AN: 1112004

Other (OTH) AF: 0.882 AC: 53262 AN: 60396

GnomAD4 genome AF: 0.839 AC: 127501 AN: 152052 Hom.: 54089 Cov.: 31 AF XY: 0.831 AC XY: 61762 AN XY: 74304

African (AFR) AF: 0.756 AC: 31332 AN: 41460

American (AMR) AF: 0.748 AC: 11413 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.945 AC: 3279 AN: 3470

East Asian (EAS) AF: 0.723 AC: 3727 AN: 5152

South Asian (SAS) AF: 0.752 AC: 3617 AN: 4810

European-Finnish (FIN) AF: 0.837 AC: 8851 AN: 10580

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.916 AC: 62311 AN: 68000

Other (OTH) AF: 0.853 AC: 1802 AN: 2112

Alfa AF: 0.890 Hom.: 201816

Bravo AF: 0.827

Asia WGS AF: 0.684 AC: 2383 AN: 3478

EpiCase AF: 0.922

EpiControl AF: 0.921

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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:2 Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 16, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not specified Benign:2

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 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 85. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.0
DANN	Benign	0.49
PhyloP100		0.34

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: rs1084004; hg19: chr10-73121945; COSMIC: COSV64385266; COSMIC: COSV64385266;