rs199861210

chr10-71362382-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018344.6(SLC29A3):c.1202G>A(p.Arg401His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R401C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: SLC29A3 NM_018344.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC29A3	NM_018344.6	c.1202G>A	p.Arg401His	missense_variant	6/6	ENST00000373189.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC29A3	ENST00000373189.6	c.1202G>A	p.Arg401His	missense_variant	6/6	1	NM_018344.6	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251404 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135888

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000309 AC: 451 AN: 1461874 Hom.: 0 Cov.: 34 AF XY: 0.000301 AC XY: 219 AN XY: 727236

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000364

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74426

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

H syndrome Uncertain:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 07, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 401 of the SLC29A3 protein (p.Arg401His). This variant is present in population databases (rs199861210, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SLC29A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 300370). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Uncertain	2.9	M;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
Polyphen		0.98	D;D;.
Vest4		0.80
MVP		0.87
MPC		0.41
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.46
gMVP		0.74

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: rs199861210; hg19: chr10-73122139;