Genetic Variant NMB:p.Pro73Thr (chr15-84657289-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_021077.4(NMB):c.217C>A(p.Pro73Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,597,686 control chromosomes in the GnomAD database, including 49,271 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.19 ( 3530 hom., cov: 31)

Exomes 𝑓: 0.25 ( 45741 hom. )

Consequence

NMB
NM_021077.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.408

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003712654).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMB	NM_021077.4 link	c.217C>A	p.Pro73Thr	missense_variant	Exon 2 of 3	ENST00000360476.8	NP_066563.2	P08949-1
NMB	NM_205858.2 link	c.217C>A	p.Pro73Thr	missense_variant	Exon 2 of 3		NP_995580.1	P08949-2
NMB	XM_017022239.2 link	c.*111C>A		downstream_gene_variant			XP_016877728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NMB	ENST00000360476.8 link	c.217C>A	p.Pro73Thr	missense_variant	Exon 2 of 3	1	NM_021077.4	ENSP00000353664.3		P08949-1
NMB	ENST00000394588.3 link	c.217C>A	p.Pro73Thr	missense_variant	Exon 2 of 3	1		ENSP00000378089.3		P08949-2

Frequencies

GnomAD3 genomes

AF:

0.191

AC:

29100

AN:

152038

Hom.:

3531

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0472

Gnomad AMI

AF:

0.459

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.224

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.271

Gnomad OTH

AF:

0.210

GnomAD3 exomes

AF:

0.220

AC:

48830

AN:

222298

Hom.:

5761

AF XY:

0.226

AC XY:

27239

AN XY:

120524

show subpopulations

Gnomad AFR exome

AF:

0.0423

Gnomad AMR exome

AF:

0.175

Gnomad ASJ exome

AF:

0.245

Gnomad EAS exome

AF:

0.125

Gnomad SAS exome

AF:

0.199

Gnomad FIN exome

AF:

0.227

Gnomad NFE exome

AF:

0.274

Gnomad OTH exome

AF:

0.250

GnomAD4 exome

AF:

0.246

AC:

355260

AN:

1445528

Hom.:

45741

Cov.:

AF XY:

0.246

AC XY:

176840

AN XY:

717900

show subpopulations

Gnomad4 AFR exome

AF:

0.0389

Gnomad4 AMR exome

AF:

0.178

Gnomad4 ASJ exome

AF:

0.249

Gnomad4 EAS exome

AF:

0.110

Gnomad4 SAS exome

AF:

0.199

Gnomad4 FIN exome

AF:

0.220

Gnomad4 NFE exome

AF:

0.264

Gnomad4 OTH exome

AF:

0.230

GnomAD4 genome

AF:

0.191

AC:

29095

AN:

152158

Hom.:

3530

Cov.:

AF XY:

0.188

AC XY:

14007

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0471

Gnomad4 AMR

AF:

0.197

Gnomad4 ASJ

AF:

0.254

Gnomad4 EAS

AF:

0.126

Gnomad4 SAS

AF:

0.183

Gnomad4 FIN

AF:

0.224

Gnomad4 NFE

AF:

0.271

Gnomad4 OTH

AF:

0.207

Alfa

AF:

0.263

Hom.:

11884

Bravo

AF:

0.185

TwinsUK

AF:

0.264

AC:

980

ALSPAC

AF:

0.252

AC:

972

ESP6500AA

AF:

0.0518

AC:

228

ESP6500EA

AF:

0.266

AC:

2288

ExAC

AF:

0.208

AC:

25237

Asia WGS

AF:

0.158

AC:

550

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.063

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.61

T;T

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.079

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.041

B;B

Vest4

0.10

MPC

0.42

ClinPred

0.015

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.097

gMVP

0.13

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over