dbSNP rs8192553: MTNR1B:p.Arg231His (chr11-92981915-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005959.5(MTNR1B):c.692G>A(p.Arg231His) variant causes a missense change. The variant allele was found at a frequency of 0.00613 in 1,614,166 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. R231S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0064 ( 33 hom. )

Consequence

MTNR1B
NM_005959.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.63

Publications

15 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010777742).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MTNR1B	NM_005959.5 link	c.692G>A	p.Arg231His	missense_variant	Exon 2 of 2	ENST00000257068.3	NP_005950.1
MTNR1B	XM_011542839.3 link	c.692G>A	p.Arg231His	missense_variant	Exon 2 of 3		XP_011541141.1
MTNR1B	XM_017017777.2 link	c.566G>A	p.Arg189His	missense_variant	Exon 2 of 3		XP_016873266.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MTNR1B	ENST00000257068.3 link	c.692G>A	p.Arg231His	missense_variant	Exon 2 of 2	1	NM_005959.5	ENSP00000257068.2
MTNR1B	ENST00000532482.1 link	n.*583G>A		non_coding_transcript_exon_variant	Exon 3 of 3	5		ENSP00000436101.1
MTNR1B	ENST00000532482.1 link	n.*583G>A		3_prime_UTR_variant	Exon 3 of 3	5		ENSP00000436101.1
MTNR1B	ENST00000528076.1 link	c.165-2892G>A		intron_variant	Intron 1 of 1	3		ENSP00000433573.1

Frequencies

GnomAD3 genomes

AF:

0.00390

AC:

594

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00555

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00667

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00393

AC:

988

AN:

251336

AF XY:

0.00406

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00565

Gnomad NFE exome

AF:

0.00662

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00636

AC:

9293

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00617

AC XY:

4488

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33480

American (AMR)

AF:

0.00174

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000788

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00465

AC:

248

AN:

53372

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00770

AC:

8568

AN:

1112006

Other (OTH)

AF:

0.00477

AC:

288

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

673

1347

2020

2694

3367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

340

680

1020

1360

1700

<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:

0.00391

AC:

595

AN:

152326

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

277

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41566

American (AMR)

AF:

0.00170

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00555

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00669

AC:

455

AN:

68036

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00556

Hom.:

Bravo

AF:

0.00385

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00385

AC:

467

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00731

EpiControl

AF:

0.00735

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Benign

-0.066

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0068

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.4

PhyloP100

3.6

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.12

Sift

Uncertain

0.015

Sift4G

Uncertain

0.0020

Vest4

0.14

ClinPred

0.053

GERP RS

0.29

Varity_R

0.18

gMVP

0.45

Mutation Taster

=92/8

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over