2-18563821-C-A

Variant names:

• chr2-18563821-C-A
• rs79501117
• NM_033253.4:c.1628G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_033253.4(NT5C1B):​c.1628G>T​(p.Gly543Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,578,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: NT5C1B NM_033253.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41

Genes affected

NT5C1B (HGNC:17818): (5'-nucleotidase, cytosolic IB) Cytosolic 5-prime nucleotidases, such as NT5C1B, catalyze production of adenosine, which regulates diverse physiologic processes (Sala-Newby and Newby, 2001 [PubMed 11690631]).[supplied by OMIM, Mar 2008]

NT5C1B-RDH14 (HGNC:38831): (NT5C1B-RDH14 readthrough) This locus represents naturally occurring read-through transcription between the neighboring NT5C1B (5'-nucleotidase, cytosolic IB) and RDH14 (retinol dehydrogenase 14) genes on chromosome 2. Alternative splicing results in multiple transcript variants, one of which encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Nov 2010]

LOC105373456 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NT5C1B	NM_033253.4	c.1628G>T	p.Gly543Val	missense_variant	Exon 9 of 9	ENST00000304081.9	NP_150278.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NT5C1B	ENST00000304081.9	c.1628G>T	p.Gly543Val	missense_variant	Exon 9 of 9	1	NM_033253.4	ENSP00000305979.4
NT5C1B-RDH14	ENST00000532967.5	c.1784+24G>T		intron_variant	Intron 10 of 10	2		ENSP00000433415.1
NT5C1B	ENST00000406971.6	n.*949G>T		non_coding_transcript_exon_variant	Exon 10 of 10	5		ENSP00000383905.2
NT5C1B	ENST00000406971.6	n.*949G>T		3_prime_UTR_variant	Exon 10 of 10	5		ENSP00000383905.2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000988 AC: 23 AN: 232704 Hom.: 0 AF XY: 0.000143 AC XY: 18 AN XY: 125768

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000341

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 186 AN: 1425890 Hom.: 0 Cov.: 30 AF XY: 0.000129 AC XY: 91 AN XY: 705608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000382

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.000137

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74472

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1859G>T (p.G620V) alteration is located in exon 10 (coding exon 10) of the NT5C1B gene. This alteration results from a G to T substitution at nucleotide position 1859, causing the glycine (G) at amino acid position 620 to be replaced by a valine (V). 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	Benign	0.19
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.4	.;M
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		1.0	D;D
Vest4		0.51
MVP		0.40
MPC		0.83
ClinPred		0.91	D
GERP RS		4.9
Varity_R		0.70
gMVP		0.95

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: rs79501117; hg19: chr2-18745087;