rs2277257

Variant names:

• chr10-71322806-A-G
• rs2277257
• NM_018344.6:c.52A>G

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.52A>G​(p.Arg18Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,613,876 control chromosomes in the GnomAD database, including 147,529 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (17987 hom., cov: 33)
  • Exomes 𝑓: 0.42 (129542 hom.)
• Consequence: SLC29A3 NM_018344.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.472
• Publications: 32 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=3.353772E-6).
• BP6: Variant 10-71322806-A-G is Benign according to our data. Variant chr10-71322806-A-G is described in ClinVar as Benign. ClinVar VariationId is 130342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC29A3	NM_018344.6	c.52A>G	p.Arg18Gly	missense_variant	Exon 2 of 6	ENST00000373189.6	NP_060814.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC29A3	ENST00000373189.6	c.52A>G	p.Arg18Gly	missense_variant	Exon 2 of 6	1	NM_018344.6	ENSP00000362285.5

Frequencies

GnomAD3 genomes AF: 0.474 AC: 71954 AN: 151934 Hom.: 17977 Cov.: 33

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.440

GnomAD2 exomes AF: 0.415 AC: 103688 AN: 249644 AF XY: 0.416

Gnomad AFR exome AF: 0.649

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.432

Gnomad EAS exome AF: 0.339

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.404

GnomAD4 exome AF: 0.417 AC: 610001 AN: 1461824 Hom.: 129542 Cov.: 71 AF XY: 0.417 AC XY: 303470 AN XY: 727210

African (AFR) AF: 0.653 AC: 21879 AN: 33480

American (AMR) AF: 0.311 AC: 13917 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 11151 AN: 26136

East Asian (EAS) AF: 0.361 AC: 14319 AN: 39700

South Asian (SAS) AF: 0.452 AC: 39020 AN: 86258

European-Finnish (FIN) AF: 0.442 AC: 23584 AN: 53370

Middle Eastern (MID) AF: 0.403 AC: 2326 AN: 5768

European-Non Finnish (NFE) AF: 0.412 AC: 457973 AN: 1111998

Other (OTH) AF: 0.428 AC: 25832 AN: 60390

GnomAD4 genome AF: 0.474 AC: 72003 AN: 152052 Hom.: 17987 Cov.: 33 AF XY: 0.473 AC XY: 35120 AN XY: 74322

African (AFR) AF: 0.645 AC: 26746 AN: 41480

American (AMR) AF: 0.382 AC: 5845 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1547 AN: 3472

East Asian (EAS) AF: 0.352 AC: 1816 AN: 5162

South Asian (SAS) AF: 0.455 AC: 2194 AN: 4822

European-Finnish (FIN) AF: 0.445 AC: 4692 AN: 10540

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27712 AN: 67972

Other (OTH) AF: 0.439 AC: 927 AN: 2112

Alfa AF: 0.421 Hom.: 60734

Bravo AF: 0.470

TwinsUK AF: 0.417 AC: 1548

ALSPAC AF: 0.418 AC: 1610

ESP6500AA AF: 0.636 AC: 2802

ESP6500EA AF: 0.411 AC: 3537

ExAC AF: 0.424 AC: 51537

Asia WGS AF: 0.422 AC: 1467 AN: 3478

EpiCase AF: 0.394

EpiControl AF: 0.400

ClinVar

Significance: Benign

Submissions summary: Benign:6

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 specified Benign:2

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 51% of patients studied by a panel of primary immunodeficiencies. Number of patients: 49. Only high quality variants are reported. -

-

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.91
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.58	.;T
MetaRNN	Benign	0.0000034	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;L
PhyloP100		0.47
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	.;N
REVEL	Benign	0.050
Sift	Benign	0.11	.;T
Polyphen		0.0010	B;B
Vest4		0.066
MPC		0.075
ClinPred		0.0030	T
GERP RS		1.2
Varity_R		0.078
gMVP		0.55

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: rs2277257; hg19: chr10-73082563; COSMIC: COSV64386000; COSMIC: COSV64386000;