Genetic Variant NME1:c.-5+989G>T (chr17-51154651-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000269.3(NME1):c.-5+989G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 152,028 control chromosomes in the GnomAD database, including 11,330 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.39 ( 11330 hom., cov: 32)

Consequence

NME1
NM_000269.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00500

Publications

16 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NME1	NM_000269.3 link	c.-5+989G>T	intron_variant	Intron 1 of 4	ENST00000393196.8	NP_000260.1	P15531-1A0A384MTW7
NME1-NME2	NM_001018136.3 link	c.-5+989G>T	intron_variant	Intron 1 of 7		NP_001018146.1	P22392-2
NME1	NM_198175.1 link	c.71+207G>T	intron_variant	Intron 2 of 5		NP_937818.1	P15531-2
NME1-NME2	NR_037149.2 link	n.324+207G>T	intron_variant	Intron 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NME1	ENST00000393196.8 link	c.-5+989G>T		intron_variant	Intron 1 of 4	1	NM_000269.3	ENSP00000376892.3		P15531-1
NME1-NME2	ENST00000393193.6 link	c.-5+989G>T		intron_variant	Intron 1 of 7	2		ENSP00000376889.2

Frequencies

GnomAD3 genomes

AF:

0.386

AC:

58684

AN:

151912

Hom.:

11316

Cov.:

show subpopulations

Gnomad AFR

AF:

0.375

Gnomad AMI

AF:

0.412

Gnomad AMR

AF:

0.407

Gnomad ASJ

AF:

0.408

Gnomad EAS

AF:

0.378

Gnomad SAS

AF:

0.306

Gnomad FIN

AF:

0.364

Gnomad MID

AF:

0.402

Gnomad NFE

AF:

0.397

Gnomad OTH

AF:

0.396

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.386

AC:

58736

AN:

152028

Hom.:

11330

Cov.:

AF XY:

0.382

AC XY:

28406

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.375

AC:

15552

AN:

41444

American (AMR)

AF:

0.406

AC:

6201

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.408

AC:

1415

AN:

3466

East Asian (EAS)

AF:

0.378

AC:

1959

AN:

5180

South Asian (SAS)

AF:

0.307

AC:

1479

AN:

4824

European-Finnish (FIN)

AF:

0.364

AC:

3843

AN:

10568

Middle Eastern (MID)

AF:

0.394

AC:

115

AN:

292

European-Non Finnish (NFE)

AF:

0.397

AC:

26953

AN:

67962

Other (OTH)

AF:

0.400

AC:

845

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1866

3731

5597

7462

9328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

572

1144

1716

2288

2860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.397

Hom.:

1436

Bravo

AF:

0.391

Asia WGS

AF:

0.359

AC:

1247

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

2.6

(source)

DANN

Benign

0.25

PhyloP100

-0.0050

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over