11-66368671-G-A

Variant names:

• chr11-66368671-G-A
• rs1020700270
• NM_001532.3:c.416C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001532.3(SLC29A2):​c.416C>T​(p.Ser139Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000693 in 1,443,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S139Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC29A2 NM_001532.3 missense, splice_region
• Scores: Splicing: ADA: 0.9882
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62
• Publications: 0 publications found

Genes affected

SLC29A2 (HGNC:11004): (solute carrier family 29 member 2) The uptake of nucleosides by transporters, such as SLC29A2, is essential for nucleotide synthesis by salvage pathways in cells that lack de novo biosynthetic pathways. Nucleoside transport also plays a key role in the regulation of many physiologic processes through its effect on adenosine concentration at the cell surface (Griffiths et al., 1997 [PubMed 9396714]).[supplied by OMIM, Nov 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001532.3. 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
	SLC29A2	NM_001532.3	MANE Select	c.416C>T	p.Ser139Phe	missense splice_region	Exon 5 of 12	NP_001523.2
	SLC29A2	NM_001300868.2		c.416C>T	p.Ser139Phe	missense splice_region	Exon 7 of 14	NP_001287797.1	Q14542-1
	SLC29A2	NM_001300869.2		c.416C>T	p.Ser139Phe	missense splice_region	Exon 7 of 13	NP_001287798.1	Q14542-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC29A2	ENST00000357440.7	TSL:1 MANE Select	c.416C>T	p.Ser139Phe	missense splice_region	Exon 5 of 12	ENSP00000350024.2	Q14542-1
	SLC29A2	ENST00000311161.11	TSL:1	c.416C>T	p.Ser139Phe	missense splice_region	Exon 6 of 12	ENSP00000311250.7	Q14542-4
	SLC29A2	ENST00000540386.5	TSL:1	n.416C>T		splice_region non_coding_transcript_exon	Exon 5 of 12	ENSP00000444870.1	Q14542-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000461 AC: 1 AN: 216698 AF XY: 0.00

Gnomad AFR exome AF: 0.0000765

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443590 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 716182

African (AFR) AF: 0.0000301 AC: 1 AN: 33196

American (AMR) AF: 0.00 AC: 0 AN: 41710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25682

East Asian (EAS) AF: 0.00 AC: 0 AN: 39000

South Asian (SAS) AF: 0.00 AC: 0 AN: 83260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103358

Other (OTH) AF: 0.00 AC: 0 AN: 59682

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.55
Sift	Benign	0.19	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.96	D
Vest4		0.79
MutPred		0.79		Loss of catalytic residue at S139 (P = 0.0468)
MVP		0.76
MPC		0.58
ClinPred		0.95	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.30
gMVP		0.76
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.84
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: rs1020700270; hg19: chr11-66136142;