10-71319312-T-G

Variant names:

• chr10-71319312-T-G
• rs1845790373
• NM_018344.6:c.1+2T>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018344.6(SLC29A3):​c.1+2T>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000807 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000081 (0 hom.)
• Consequence: SLC29A3 NM_018344.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.97
• Publications: 0 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• dysosteosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298105 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 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
• PP5: Variant 10-71319312-T-G is Pathogenic according to our data. Variant chr10-71319312-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2136876.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1+2T>G		splice_donor intron	N/A	NP_060814.4
	SLC29A3	NM_001363518.2		c.-653T>G		5_prime_UTR	Exon 1 of 6	NP_001350447.1	A0A2R8YDR8
	SLC29A3	NM_001174098.2		c.1+2T>G		splice_donor intron	N/A	NP_001167569.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000807 AC: 4 AN: 495782 Hom.: 0 Cov.: 0 AF XY: 0.00000369 AC XY: 1 AN XY: 270784

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11166

American (AMR) AF: 0.00 AC: 0 AN: 27728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18200

East Asian (EAS) AF: 0.00 AC: 0 AN: 25438

South Asian (SAS) AF: 0.00 AC: 0 AN: 56992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2316

European-Non Finnish (NFE) AF: 0.0000102 AC: 3 AN: 292950

Other (OTH) AF: 0.0000359 AC: 1 AN: 27834

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00376316), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	H syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	33
DANN	Benign	0.93
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.14	N
PhyloP100		2.0
GERP RS		2.4
PromoterAI		0.51	Over-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		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

Other links and lift over

dbSNP: rs1845790373; hg19: chr10-73079069;