Genetic Variant NMB:p.Met120Ile (chr15-84655375-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000394588.3(NMB):c.360G>A(p.Met120Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0612 in 1,614,058 control chromosomes in the GnomAD database, including 3,373 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.066 ( 409 hom., cov: 33)

Exomes 𝑓: 0.061 ( 2964 hom. )

Consequence

NMB
ENST00000394588.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.94

Publications

22 publications found

Variant links:

Genes affected

NMB (HGNC:7842): (neuromedin B) This gene encodes a member of the bombesin-like family of neuropeptides, which negatively regulate eating behavior. The encoded protein may regulate colonic smooth muscle contraction through binding to its cognate receptor, the neuromedin B receptor (NMBR). Polymorphisms of this gene may be associated with hunger, weight gain and obesity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

NMB links:

ENSG00000291159 (HGNC:):

ENSG00000291159 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0028395653).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMB	NM_021077.4 link	c.365G>A	p.Ter122Ter	stop_retained_variant	Exon 3 of 3	ENST00000360476.8	NP_066563.2	P08949-1
NMB	NM_205858.2 link	c.360G>A	p.Met120Ile	missense_variant	Exon 3 of 3		NP_995580.1	P08949-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NMB	ENST00000394588.3 link	c.360G>A	p.Met120Ile	missense_variant	Exon 3 of 3	1		ENSP00000378089.3	P08949-2
NMB	ENST00000360476.8 link	c.365G>A	p.Ter122Ter	stop_retained_variant	Exon 3 of 3	1	NM_021077.4	ENSP00000353664.3	P08949-1
ENSG00000291159	ENST00000762213.1 link	n.983-3953C>T		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0655

AC:

9971

AN:

152174

Hom.:

408

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0917

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.0433

Gnomad ASJ

AF:

0.0948

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.0538

Gnomad FIN

AF:

0.0515

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0616

Gnomad OTH

AF:

0.0635

GnomAD2 exomes

AF:

0.0532

AC:

13363

AN:

251274

AF XY:

0.0531

show subpopulations

Gnomad AFR exome

AF:

0.0883

Gnomad AMR exome

AF:

0.0330

Gnomad ASJ exome

AF:

0.0918

Gnomad EAS exome

AF:

0.00277

Gnomad FIN exome

AF:

0.0537

Gnomad NFE exome

AF:

0.0592

Gnomad OTH exome

AF:

0.0538

GnomAD4 exome

AF:

0.0607

AC:

88722

AN:

1461766

Hom.:

2964

Cov.:

AF XY:

0.0604

AC XY:

43903

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.0920

AC:

3081

AN:

33476

American (AMR)

AF:

0.0347

AC:

1553

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0879

AC:

2295

AN:

26122

East Asian (EAS)

AF:

0.00106

AC:

AN:

39700

South Asian (SAS)

AF:

0.0551

AC:

4753

AN:

86256

European-Finnish (FIN)

AF:

0.0516

AC:

2754

AN:

53414

Middle Eastern (MID)

AF:

0.0512

AC:

295

AN:

5764

European-Non Finnish (NFE)

AF:

0.0632

AC:

70230

AN:

1111926

Other (OTH)

AF:

0.0616

AC:

3719

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

4280

8560

12839

17119

21399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2678

5356

8034

10712

13390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0655

AC:

9979

AN:

152292

Hom.:

409

Cov.:

AF XY:

0.0643

AC XY:

4789

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0917

AC:

3812

AN:

41554

American (AMR)

AF:

0.0431

AC:

660

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0948

AC:

329

AN:

3470

East Asian (EAS)

AF:

0.00270

AC:

AN:

5180

South Asian (SAS)

AF:

0.0536

AC:

259

AN:

4828

European-Finnish (FIN)

AF:

0.0515

AC:

547

AN:

10614

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0616

AC:

4189

AN:

68030

Other (OTH)

AF:

0.0629

AC:

133

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

465

931

1396

1862

2327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<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:

0.0618

Hom.:

976

Bravo

AF:

0.0648

TwinsUK

AF:

0.0674

AC:

250

ALSPAC

AF:

0.0690

AC:

266

ESP6500AA

AF:

0.0897

AC:

395

ESP6500EA

AF:

0.0658

AC:

566

ExAC

AF:

0.0529

AC:

6429

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0598

EpiControl

AF:

0.0595

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.54

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

PhyloP100

2.9

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.30

REVEL

Benign

0.099

Sift

Benign

0.20

Sift4G

Benign

0.088

Polyphen

0.0

Vest4

0.039

MutPred

0.24

Gain of sheet (P = 0.0149);

MPC

0.17

ClinPred

0.0058

GERP RS

2.7

gMVP

0.057

Mutation Taster

=95/5

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over