Genetic Variant SLC29A3:c.1+2T>A (chr10-71319312-T-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_018344.6(SLC29A3):c.1+2T>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000202 in 495,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000020 ( 0 hom. )

Consequence

SLC29A3
NM_018344.6 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.97

Publications

0 publications found

Variant links:

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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
dysosteosclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC29A3 links:

ENSG00000298105 (HGNC:):

ENSG00000298105 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC29A3	NM_018344.6	MANE Select	c.1+2T>A	splice_donor intron	N/A	NP_060814.4
SLC29A3	NM_001363518.2		c.-653T>A	5_prime_UTR	Exon 1 of 6	NP_001350447.1	A0A2R8YDR8
SLC29A3	NM_001174098.2		c.1+2T>A	splice_donor intron	N/A	NP_001167569.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC29A3	ENST00000373189.6	TSL:1 MANE Select	c.1+2T>A	splice_donor intron	N/A	ENSP00000362285.5	Q9BZD2-1
SLC29A3	ENST00000479577.2	TSL:2	c.-653T>A	5_prime_UTR	Exon 1 of 6	ENSP00000493995.1	A0A2R8YDR8
SLC29A3	ENST00000697843.1		n.28T>A	non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000202

AC:

AN:

495782

Hom.:

Cov.:

AF XY:

0.00000369

AC XY:

AN XY:

270784

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11166

American (AMR)

AF:

0.00

AC:

AN:

27728

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18200

East Asian (EAS)

AF:

0.00

AC:

AN:

25438

South Asian (SAS)

AF:

0.00

AC:

AN:

56992

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

292950

Other (OTH)

AF:

0.0000359

AC:

AN:

27834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Benign

0.94

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.14

PhyloP100

2.0

GERP RS

2.4

PromoterAI

-0.82

Under-expression

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.51

Position offset: 2

DS_DL_spliceai

0.99

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over