NM_018344.6:c.300+3A>G

Variant names:

• chr10-71323057-A-G
• rs7083031
• NM_018344.6:c.300+3A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_018344.6(SLC29A3):​c.300+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00191 in 1,612,724 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (30 hom., cov: 34)
  • Exomes 𝑓: 0.00099 (31 hom.)
• Consequence: SLC29A3 NM_018344.6 splice_region, intron
• Scores: Splicing: ADA: 0.8215
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.20
• Publications: 3 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 10-71323057-A-G is Benign according to our data. Variant chr10-71323057-A-G is described in ClinVar as Benign. ClinVar VariationId is 300357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1637/152362) while in subpopulation AFR AF = 0.0378 (1571/41588). AF 95% confidence interval is 0.0362. There are 30 homozygotes in GnomAd4. There are 754 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC29A3	NM_018344.6	MANE Select	c.300+3A>G		splice_region intron	N/A	NP_060814.4
	SLC29A3	NM_001363518.2		c.66+3A>G		splice_region intron	N/A	NP_001350447.1
	SLC29A3	NM_001174098.2		c.300+3A>G		splice_region intron	N/A	NP_001167569.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC29A3	ENST00000373189.6	TSL:1 MANE Select	c.300+3A>G		splice_region intron	N/A	ENSP00000362285.5
	SLC29A3	ENST00000479577.2	TSL:2	c.66+3A>G		splice_region intron	N/A	ENSP00000493995.1
	SLC29A3	ENST00000642198.1		n.66+3A>G		splice_region intron	N/A	ENSP00000494827.1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1635 AN: 152244 Hom.: 30 Cov.: 34

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00261 AC: 649 AN: 248240 AF XY: 0.00181

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000988 AC: 1443 AN: 1460362 Hom.: 31 Cov.: 35 AF XY: 0.000796 AC XY: 578 AN XY: 726486

African (AFR) AF: 0.0358 AC: 1198 AN: 33448

American (AMR) AF: 0.00114 AC: 51 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52898

Middle Eastern (MID) AF: 0.00182 AC: 9 AN: 4948

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1112002

Other (OTH) AF: 0.00191 AC: 115 AN: 60292

GnomAD4 genome AF: 0.0107 AC: 1637 AN: 152362 Hom.: 30 Cov.: 34 AF XY: 0.0101 AC XY: 754 AN XY: 74514

African (AFR) AF: 0.0378 AC: 1571 AN: 41588

American (AMR) AF: 0.00202 AC: 31 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68028

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00594 Hom.: 8

Bravo AF: 0.0119

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	H syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Benign	0.96
PhyloP100		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.080		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: rs7083031; hg19: chr10-73082814;