17-51161814-C-T

Position:

chr17-51161814-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_000269.3(NME1):c.428C>T(p.Thr143Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,613,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NME1
NM_000269.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.131

Variant links:

Genes affected

NME1 (HGNC:7849): (NME/NM23 nucleoside diphosphate kinase 1) This gene (NME1) was identified because of its reduced mRNA transcript levels in highly metastatic cells. Nucleoside diphosphate kinase (NDK) exists as a hexamer composed of 'A' (encoded by this gene) and 'B' (encoded by NME2) isoforms. Mutations in this gene have been identified in aggressive neuroblastomas. Two transcript variants encoding different isoforms have been found for this gene. Co-transcription of this gene and the neighboring downstream gene (NME2) generates naturally-occurring transcripts (NME1-NME2), which encodes a fusion protein comprised of sequence sharing identity with each individual gene product. [provided by RefSeq, Jul 2008]

NME1 links:

NME1-NME2 (HGNC:33531): (NME1-NME2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring NME1 and NME2 genes. The significance of this read-through transcription and the function of the resulting protein product have not yet been determined. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Nov 2010]

NME1-NME2 links:

NME1-NME2 (HGNC:):

NME1-NME2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15888566).

BP6

Variant 17-51161814-C-T is Benign according to our data. Variant chr17-51161814-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2592832.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NME1	NM_000269.3 linkuse as main transcript	c.428C>T	p.Thr143Met	missense_variant	5/5	ENST00000393196.8	NP_000260.1	P15531-1A0A384MTW7
NME1	NM_198175.1 linkuse as main transcript	c.503C>T	p.Thr168Met	missense_variant	6/6		NP_937818.1	P15531-2
NME1-NME2	NM_001018136.3 linkuse as main transcript	c.341+542C>T		intron_variant			NP_001018146.1	P22392-2
NME1-NME2	NR_037149.2 linkuse as main transcript	n.669+542C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NME1	ENST00000393196.8 linkuse as main transcript	c.428C>T	p.Thr143Met	missense_variant	5/5	1	NM_000269.3	ENSP00000376892.3		P15531-1
NME1-NME2	ENST00000555572.1 linkuse as main transcript	c.416+542C>T		intron_variant		2		ENSP00000451932.1		Q32Q12

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251474

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000110

AC:

161

AN:

1461052

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

726858

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000134

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000711

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Uncertain

0.51

D;.;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.056

T;.;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.1

M;.;.

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.016

D;D;D

Sift4G

Uncertain

0.042

D;D;D

Polyphen

0.60

P;P;P

Vest4

0.11

MutPred

0.25

Gain of catalytic residue at T143 (P = 0.0565);.;.;

MVP

0.82

MPC

0.40

ClinPred

0.084

GERP RS

-0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.055

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over