rs140510680

Variant names:

• chr2-18576819-C-G
• rs140510680
• NM_033253.4:c.1098G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033253.4(NT5C1B):​c.1098G>C​(p.Leu366Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: NT5C1B NM_033253.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.10
• Publications: 0 publications found

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]

ENSG00000304698 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033253.4. 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
	NT5C1B	NM_033253.4	MANE Select	c.1098G>C	p.Leu366Phe	missense	Exon 7 of 9	NP_150278.2	Q96P26-2
	NT5C1B-RDH14	NM_001199103.2		c.1104G>C	p.Leu368Phe	missense	Exon 7 of 9	NP_001186032.1
	NT5C1B	NM_001199087.2		c.1329G>C	p.Leu443Phe	missense	Exon 8 of 10	NP_001186016.1	B4DZ86

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NT5C1B	ENST00000304081.9	TSL:1 MANE Select	c.1098G>C	p.Leu366Phe	missense	Exon 7 of 9	ENSP00000305979.4	Q96P26-2
	NT5C1B	ENST00000359846.6	TSL:1	c.1278G>C	p.Leu426Phe	missense	Exon 8 of 10	ENSP00000352904.2	Q96P26-1
	NT5C1B-RDH14	ENST00000532967.5	TSL:2	c.1278G>C	p.Leu426Phe	missense	Exon 8 of 11	ENSP00000433415.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251238 AF XY: 0.0000295

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000718 AC: 105 AN: 1461608 Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46 AN XY: 727090

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.000157 AC: 7 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000791 AC: 88 AN: 1111822

Other (OTH) AF: 0.000149 AC: 9 AN: 60388

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74326

African (AFR) AF: 0.000145 AC: 6 AN: 41442

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	0.21
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.095
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		-1.1
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.23	B
Vest4		0.38
MutPred		0.92		Loss of stability (P = 0.2118)
MVP		0.72
MPC		0.65
ClinPred		0.98	D
GERP RS		-1.8
Varity_R		0.74
gMVP		0.91
Mutation Taster		=35/65	disease causing

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

Other links and lift over

dbSNP: rs140510680; hg19: chr2-18758085;