rs780668

Variant names:

• chr10-71351651-C-T
• rs780668
• NM_018344.6:c.473C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018344.6(SLC29A3):​c.473C>T​(p.Ser158Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.701 in 1,613,958 control chromosomes in the GnomAD database, including 409,244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,drug response (★★). Synonymous variant affecting the same amino acid position (i.e. S158S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.61 (31114 hom., cov: 32)
  • Exomes 𝑓: 0.71 (378130 hom.)
• Consequence: SLC29A3 NM_018344.6 missense
• Clinical Significance: Benign; drug response criteria provided, multiple submitters, no conflicts B:8 O:3
• Conservation: PhyloP100: 7.50
• Publications: 57 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• dysosteosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.6845643E-6).
• BP6: Variant 10-71351651-C-T is Benign according to our data. Variant chr10-71351651-C-T is described in ClinVar as Benign|drug_response. ClinVar VariationId is 130341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

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.473C>T	p.Ser158Phe	missense	Exon 4 of 6	NP_060814.4
	SLC29A3	NM_001363518.2		c.239C>T	p.Ser80Phe	missense	Exon 4 of 6	NP_001350447.1	A0A2R8YDR8
	SLC29A3	NM_001174098.2		c.473C>T	p.Ser158Phe	missense	Exon 4 of 6	NP_001167569.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC29A3	ENST00000373189.6	TSL:1 MANE Select	c.473C>T	p.Ser158Phe	missense	Exon 4 of 6	ENSP00000362285.5	Q9BZD2-1
	SLC29A3	ENST00000479577.2	TSL:2	c.239C>T	p.Ser80Phe	missense	Exon 4 of 6	ENSP00000493995.1	A0A2R8YDR8
	SLC29A3	ENST00000642198.1		n.156C>T		non_coding_transcript_exon	Exon 3 of 6	ENSP00000494827.1	A0A2R8Y5U2

Frequencies

GnomAD3 genomes AF: 0.613 AC: 93188 AN: 151976 Hom.: 31124 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.741

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.760

Gnomad OTH AF: 0.645

GnomAD2 exomes AF: 0.639 AC: 160758 AN: 251472 AF XY: 0.650

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.485

Gnomad ASJ exome AF: 0.733

Gnomad EAS exome AF: 0.456

Gnomad FIN exome AF: 0.741

Gnomad NFE exome AF: 0.755

Gnomad OTH exome AF: 0.697

GnomAD4 exome AF: 0.711 AC: 1038771 AN: 1461864 Hom.: 378130 Cov.: 63 AF XY: 0.708 AC XY: 514870 AN XY: 727236

African (AFR) AF: 0.356 AC: 11914 AN: 33480

American (AMR) AF: 0.492 AC: 21998 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 19174 AN: 26136

East Asian (EAS) AF: 0.364 AC: 14468 AN: 39700

South Asian (SAS) AF: 0.539 AC: 46495 AN: 86256

European-Finnish (FIN) AF: 0.744 AC: 39722 AN: 53418

Middle Eastern (MID) AF: 0.714 AC: 4117 AN: 5768

European-Non Finnish (NFE) AF: 0.755 AC: 839266 AN: 1111986

Other (OTH) AF: 0.689 AC: 41617 AN: 60396

GnomAD4 genome AF: 0.613 AC: 93189 AN: 152094 Hom.: 31114 Cov.: 32 AF XY: 0.610 AC XY: 45321 AN XY: 74356

African (AFR) AF: 0.362 AC: 15001 AN: 41458

American (AMR) AF: 0.586 AC: 8955 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2556 AN: 3472

East Asian (EAS) AF: 0.428 AC: 2210 AN: 5162

South Asian (SAS) AF: 0.523 AC: 2515 AN: 4810

European-Finnish (FIN) AF: 0.741 AC: 7858 AN: 10606

Middle Eastern (MID) AF: 0.685 AC: 200 AN: 292

European-Non Finnish (NFE) AF: 0.760 AC: 51693 AN: 67998

Other (OTH) AF: 0.643 AC: 1359 AN: 2114

Alfa AF: 0.703 Hom.: 156226

Bravo AF: 0.588

TwinsUK AF: 0.746 AC: 2766

ALSPAC AF: 0.752 AC: 2900

ESP6500AA AF: 0.367 AC: 1615

ESP6500EA AF: 0.747 AC: 6426

ExAC AF: 0.638 AC: 77492

Asia WGS AF: 0.460 AC: 1602 AN: 3478

EpiCase AF: 0.756

EpiControl AF: 0.759

ClinVar

ClinVar submissions

Significance: Benign; drug response

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	H syndrome (3)
-	-	1	not provided (2)
-	-	-	Acanthosis nigricans (1)
-	-	-	Gemcitabine response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0000037	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.29
Sift	Benign	0.062	T
Polyphen		0.66	P
Vest4		0.31
MPC		0.39
ClinPred		0.064	T
GERP RS		4.6
Varity_R		0.30
gMVP		0.61

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

Other links and lift over

dbSNP: rs780668; hg19: chr10-73111408; COSMIC: COSV64385485; COSMIC: COSV64385485;