10-71322794-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018344.6(SLC29A3):c.40A>G(p.Asn14Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: SLC29A3 NM_018344.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054583907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC29A3	NM_018344.6	c.40A>G	p.Asn14Asp	missense_variant	2/6	ENST00000373189.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC29A3	ENST00000373189.6	c.40A>G	p.Asn14Asp	missense_variant	2/6	1	NM_018344.6	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249500 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135038

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727224

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74432

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000129 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

H syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 14 of the SLC29A3 protein (p.Asn14Asp). This variant is present in population databases (rs541461094, 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: 536248). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC29A3 protein function with a negative predictive value of 80%. 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	0.099
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.033	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.055	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.64	N
PrimateAI	Uncertain	0.53	T
Polyphen		0.33	B;B
Vest4		0.19
MVP		0.51
MPC		0.088
ClinPred		0.052	T
GERP RS		4.1
Varity_R		0.091
gMVP		0.41

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: rs541461094; hg19: chr10-73082551;