2-18584219-A-T

Position:

• chr2-18584219-A-T

Variant summary

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

The NM_033253.4(NT5C1B):​c.760T>A​(p.Ser254Thr) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S254F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NT5C1B NM_033253.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

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:):

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, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NT5C1B	NM_033253.4	c.760T>A	p.Ser254Thr	missense_variant	5/9	ENST00000304081.9
NT5C1B-RDH14	NM_001199103.2	c.766T>A	p.Ser256Thr	missense_variant	5/9
LOC105373456	XR_007086234.1	n.722+20193A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NT5C1B	ENST00000304081.9	c.760T>A	p.Ser254Thr	missense_variant	5/9	1	NM_033253.4	P2
NT5C1B	ENST00000359846.6	c.940T>A	p.Ser314Thr	missense_variant	6/10	1		A2
NT5C1B	ENST00000490687.1	n.1293T>A		non_coding_transcript_exon_variant	3/3	2
NT5C1B	ENST00000406971.6	c.*81T>A		3_prime_UTR_variant, NMD_transcript_variant	6/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 27, 2022

The c.991T>A (p.S331T) alteration is located in exon 6 (coding exon 6) of the NT5C1B gene. This alteration results from a T to A substitution at nucleotide position 991, causing the serine (S) at amino acid position 331 to be replaced by a threonine (T). 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	0.22
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Uncertain	-2.5	N;N;N;N
REVEL	Pathogenic	0.82
Sift	Uncertain	0.021	D;D;D;D
Sift4G	Uncertain	0.041	D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D
Vest4		0.89
MutPred		0.85		Gain of helix (P = 0.062);.;.;Gain of helix (P = 0.062);
MVP		0.88
MPC		0.61
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.31
gMVP		0.70

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-18765485;