rs2487068

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:10 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018344.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC29A3	NM_018344.6	MANE Select	c.976A>G	p.Ile326Val	missense	Exon 6 of 6	NP_060814.4
	SLC29A3	NM_001363518.2		c.742A>G	p.Ile248Val	missense	Exon 6 of 6	NP_001350447.1	A0A2R8YDR8
	SLC29A3	NM_001174098.2		c.*205A>G		3_prime_UTR	Exon 6 of 6	NP_001167569.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC29A3	ENST00000373189.6	TSL:1 MANE Select	c.976A>G	p.Ile326Val	missense	Exon 6 of 6	ENSP00000362285.5	Q9BZD2-1
	SLC29A3	ENST00000479577.2	TSL:2	c.742A>G	p.Ile248Val	missense	Exon 6 of 6	ENSP00000493995.1	A0A2R8YDR8
	SLC29A3	ENST00000469204.1	TSL:2	n.473A>G		non_coding_transcript_exon	Exon 3 of 3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	H syndrome (3)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	9.7e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.52	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
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;