11-66368548-A-C

Position:

• chr11-66368548-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001532.3(SLC29A2):​c.539T>G​(p.Leu180Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC29A2 NM_001532.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC29A2	NM_001532.3	c.539T>G	p.Leu180Arg	missense_variant	5/12	ENST00000357440.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC29A2	ENST00000357440.7	c.539T>G	p.Leu180Arg	missense_variant	5/12	1	NM_001532.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The c.539T>G (p.L180R) alteration is located in exon 5 (coding exon 5) of the SLC29A2 gene. This alteration results from a T to G substitution at nucleotide position 539, causing the leucine (L) at amino acid position 180 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;D;T;D;D
Eigen	Benign	0.053
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.85	.;.;T;.;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.7	.;L;.;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D;D;.;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.014	D;D;.;D;D
Sift4G	Uncertain	0.034	D;D;D;D;D
Polyphen		0.86	P;P;P;P;P
Vest4		0.85
MutPred		0.89		Gain of methylation at L180 (P = 0.0183);Gain of methylation at L180 (P = 0.0183);Gain of methylation at L180 (P = 0.0183);Gain of methylation at L180 (P = 0.0183);Gain of methylation at L180 (P = 0.0183);
MVP		0.61
MPC		0.52
ClinPred		0.94	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs901637034; hg19: chr11-66136019;