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 ENST00000373189.6(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 ENST00000373189.6 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000373189.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC29A3	NM_018344.6	MANE Select	c.52A>G	p.Arg18Gly	missense	Exon 2 of 6	NP_060814.4
	SLC29A3	NM_001174098.2		c.52A>G	p.Arg18Gly	missense	Exon 2 of 6	NP_001167569.1
	SLC29A3	NR_033413.2		n.103A>G		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC29A3	ENST00000373189.6	TSL:1 MANE Select	c.52A>G	p.Arg18Gly	missense	Exon 2 of 6	ENSP00000362285.5
	SLC29A3	ENST00000642198.1		n.-183A>G		non_coding_transcript_exon	Exon 2 of 6	ENSP00000494827.1
	SLC29A3	ENST00000642772.1		n.52A>G		non_coding_transcript_exon	Exon 2 of 5	ENSP00000495041.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	H syndrome (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	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
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;