NM_018344.6:c.976A>G

Variant names:

• chr10-71362156-A-G
• rs2487068
• NM_018344.6:c.976A>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.976A>G​(p.Ile326Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 1,613,932 control chromosomes in the GnomAD database, including 600,978 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57523 hom., cov: 30)
  • Exomes 𝑓: 0.86 (543455 hom.)
• Consequence: SLC29A3 NM_018344.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.576
• Publications: 40 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=9.737729E-7).
• BP6: Variant 10-71362156-A-G is Benign according to our data. Variant chr10-71362156-A-G is described in ClinVar as Benign. ClinVar VariationId is 130347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC29A3	NM_018344.6	c.976A>G	p.Ile326Val	missense_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.976A>G	p.Ile326Val	missense_variant	Exon 6 of 6	1	NM_018344.6	ENSP00000362285.5

Frequencies

GnomAD3 genomes AF: 0.866 AC: 131570 AN: 151944 Hom.: 57479 Cov.: 30

Gnomad AFR AF: 0.926

Gnomad AMI AF: 0.989

Gnomad AMR AF: 0.745

Gnomad ASJ AF: 0.885

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.769

Gnomad FIN AF: 0.855

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.875

Gnomad OTH AF: 0.868

GnomAD2 exomes AF: 0.819 AC: 205805 AN: 251350 AF XY: 0.824

Gnomad AFR exome AF: 0.927

Gnomad AMR exome AF: 0.641

Gnomad ASJ exome AF: 0.889

Gnomad EAS exome AF: 0.713

Gnomad FIN exome AF: 0.856

Gnomad NFE exome AF: 0.871

Gnomad OTH exome AF: 0.841

GnomAD4 exome AF: 0.860 AC: 1257180 AN: 1461870 Hom.: 543455 Cov.: 80 AF XY: 0.858 AC XY: 624306 AN XY: 727230

African (AFR) AF: 0.926 AC: 31016 AN: 33478

American (AMR) AF: 0.646 AC: 28891 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 23053 AN: 26136

East Asian (EAS) AF: 0.678 AC: 26920 AN: 39698

South Asian (SAS) AF: 0.786 AC: 67785 AN: 86256

European-Finnish (FIN) AF: 0.859 AC: 45871 AN: 53416

Middle Eastern (MID) AF: 0.892 AC: 5147 AN: 5768

European-Non Finnish (NFE) AF: 0.878 AC: 976259 AN: 1112000

Other (OTH) AF: 0.865 AC: 52238 AN: 60394

GnomAD4 genome AF: 0.866 AC: 131669 AN: 152062 Hom.: 57523 Cov.: 30 AF XY: 0.862 AC XY: 64025 AN XY: 74312

African (AFR) AF: 0.926 AC: 38422 AN: 41494

American (AMR) AF: 0.745 AC: 11363 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.885 AC: 3070 AN: 3470

East Asian (EAS) AF: 0.705 AC: 3633 AN: 5154

South Asian (SAS) AF: 0.769 AC: 3694 AN: 4806

European-Finnish (FIN) AF: 0.855 AC: 9044 AN: 10576

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.875 AC: 59464 AN: 67986

Other (OTH) AF: 0.865 AC: 1826 AN: 2112

Alfa AF: 0.866 Hom.: 163067

Bravo AF: 0.860

TwinsUK AF: 0.871 AC: 3230

ALSPAC AF: 0.873 AC: 3364

ESP6500AA AF: 0.922 AC: 4062

ESP6500EA AF: 0.877 AC: 7543

ExAC AF: 0.825 AC: 100108

Asia WGS AF: 0.702 AC: 2445 AN: 3478

EpiCase AF: 0.876

EpiControl AF: 0.876

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 92% of patients studied by a panel of primary immunodeficiencies. Number of patients: 88. 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. -

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

-

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. -

-

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0010
DANN	Benign	0.36
DEOGEN2	Benign	0.013	T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.37	.;T;T
MetaRNN	Benign	9.7e-7	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.52	N;N;.
PhyloP100		-0.58
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.080	.;N;.
REVEL	Benign	0.027
Sift	Benign	1.0	.;T;.
Polyphen		0.0020	B;B;.
Vest4		0.012
MPC		0.053
ClinPred		0.021	T
GERP RS		-9.0
Varity_R		0.027
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2487068; hg19: chr10-73121913; COSMIC: COSV64386549; COSMIC: COSV64386549;