Genetic Variant MTNR1B:p.Arg29Leu (chr11-92969811-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005959.5(MTNR1B):c.86G>T(p.Arg29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,416,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R29Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

MTNR1B
NM_005959.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.837

Publications

0 publications found

Variant links:

Genes affected

MTNR1B (HGNC:7464): (melatonin receptor 1B) This gene encodes one of two high affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This gene product is an integral membrane protein that is a G-protein coupled, 7-transmembrane receptor. It is found primarily in the retina and brain although this detection requires RT-PCR. It is thought to participate in light-dependent functions in the retina and may be involved in the neurobiological effects of melatonin. [provided by RefSeq, Jul 2008]

MTNR1B links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059983432).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005959.5. 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
	MTNR1B	NM_005959.5	MANE Select	c.86G>T	p.Arg29Leu	missense	Exon 1 of 2	NP_005950.1	P49286

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTNR1B	ENST00000257068.3	TSL:1 MANE Select	c.86G>T	p.Arg29Leu	missense	Exon 1 of 2	ENSP00000257068.2	P49286
MTNR1B	ENST00000528076.1	TSL:3	c.27G>T	p.Ala9Ala	synonymous	Exon 1 of 2	ENSP00000433573.1	H0YDG4
MTNR1B	ENST00000532482.1	TSL:5	n.86G>T		non_coding_transcript_exon	Exon 1 of 3	ENSP00000436101.1	E9PR36

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.06e-7

AC:

AN:

1416846

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

702098

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30858

American (AMR)

AF:

0.00

AC:

AN:

41210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24970

East Asian (EAS)

AF:

0.0000272

AC:

AN:

36754

South Asian (SAS)

AF:

0.00

AC:

AN:

81386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5478

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088828

Other (OTH)

AF:

0.00

AC:

AN:

58164

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.46

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.038

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.40

M_CAP

Benign

0.010

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.49

PhyloP100

-0.84

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.28

REVEL

Benign

0.044

Sift

Benign

0.32

Sift4G

Benign

0.29

Polyphen

0.0

Vest4

0.10

MutPred

0.42

Loss of MoRF binding (P = 0.0266)

MVP

0.38

MPC

0.20

ClinPred

0.43

GERP RS

-8.4

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.042

gMVP

0.45

Mutation Taster

=93/7

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over