rs2277257

chr10-71322806-A-G

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.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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:5
• Conservation: PhyloP100: 0.472

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=3.353772E-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 id 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/exons	MANE	UniProt
SLC29A3	NM_018344.6	c.52A>G	p.Arg18Gly	missense_variant	2/6	ENST00000373189.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC29A3	ENST00000373189.6	c.52A>G	p.Arg18Gly	missense_variant	2/6	1	NM_018344.6	P1

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

GnomAD3 exomes AF: 0.415 AC: 103688 AN: 249644 Hom.: 22353 AF XY: 0.416 AC XY: 56224 AN XY: 135104

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 SAS exome AF: 0.453

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

Gnomad4 AFR exome AF: 0.653

Gnomad4 AMR exome AF: 0.311

Gnomad4 ASJ exome AF: 0.427

Gnomad4 EAS exome AF: 0.361

Gnomad4 SAS exome AF: 0.452

Gnomad4 FIN exome AF: 0.442

Gnomad4 NFE exome AF: 0.412

Gnomad4 OTH exome AF: 0.428

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

Gnomad4 AFR AF: 0.645

Gnomad4 AMR AF: 0.382

Gnomad4 ASJ AF: 0.446

Gnomad4 EAS AF: 0.352

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.445

Gnomad4 NFE AF: 0.408

Gnomad4 OTH AF: 0.439

Alfa AF: 0.411 Hom.: 26835

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

H syndrome Benign:3

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. -
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 51% of patients studied by a panel of primary immunodeficiencies. Number of patients: 49. 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. -

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
MetaRNN	Benign	0.0000034	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.31	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

Publications

LitVar

Other links and lift over

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