6-142076033-C-A

Variant names:

• chr6-142076033-C-A
• rs746892172
• NM_002511.4:c.788G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002511.4(NMBR):​c.788G>T​(p.Arg263Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000056 in 1,428,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R263P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: NMBR NM_002511.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.76
• Publications: 0 publications found

Genes affected

NMBR (HGNC:7843): (neuromedin B receptor) This gene encodes a 7-transmembrane G protein-coupled receptor that binds neuromedin B, which is a growth factor and mitogen for gastrointestinal epithelial tissue and for normal and neoplastic lung. This receptor may play a role in smooth muscle contraction, neuronal responses, and the regulation of cell growth. Antagonists of this receptor have a potential therapeutic use in inhibiting tumor cell growth. Polymorphisms in this gene may be associated with a susceptibility for schizophrenia. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002511.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NMBR	NM_002511.4	MANE Select	c.788G>T	p.Arg263Leu	missense	Exon 4 of 4	NP_002502.2	P28336
	NMBR	NM_001324307.2		c.344G>T	p.Arg115Leu	missense	Exon 4 of 4	NP_001311236.1
	NMBR	NM_001324308.2		c.344G>T	p.Arg115Leu	missense	Exon 3 of 3	NP_001311237.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NMBR	ENST00000258042.2	TSL:1 MANE Select	c.788G>T	p.Arg263Leu	missense	Exon 4 of 4	ENSP00000258042.1	P28336
	NMBR	ENST00000480652.1	TSL:5	n.-111G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000182 AC: 4 AN: 219542 AF XY: 0.00000840

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.0000720

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000983

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000560 AC: 8 AN: 1428326 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 708028

African (AFR) AF: 0.0000315 AC: 1 AN: 31744

American (AMR) AF: 0.0000794 AC: 3 AN: 37778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24290

East Asian (EAS) AF: 0.0000763 AC: 3 AN: 39312

South Asian (SAS) AF: 0.00 AC: 0 AN: 80540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097830

Other (OTH) AF: 0.00 AC: 0 AN: 58864

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		4.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.68		Loss of MoRF binding (P = 0.0287)
MVP		0.67
MPC		0.20
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.80
gMVP		0.89
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746892172; hg19: chr6-142397170;