dbSNP rs1800885: MTNR1A:p.Arg54Trp (chr4-186555206-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_005958.4(MTNR1A):c.160C>T(p.Arg54Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,595,554 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00033 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 23 hom. )

Consequence

MTNR1A
NM_005958.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.917

Publications

11 publications found

Variant links:

Genes affected

MTNR1A (HGNC:7463): (melatonin receptor 1A) This gene encodes one of two high affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This receptor is a G-protein coupled, 7-transmembrane receptor that is responsible for melatonin effects on mammalian circadian rhythm and reproductive alterations affected by day length. The receptor is an integral membrane protein that is readily detectable and localized to two specific regions of the brain. The hypothalamic suprachiasmatic nucleus appears to be involved in circadian rhythm while the hypophysial pars tuberalis may be responsible for the reproductive effects of melatonin. [provided by RefSeq, Jul 2008]

MTNR1A links:

ENSG00000272297 (HGNC:):

ENSG00000272297 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=0.010698348).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000726 (1048/1443302) while in subpopulation EAS AF = 0.0242 (942/38848). AF 95% confidence interval is 0.023. There are 23 homozygotes in GnomAdExome4. There are 533 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 23 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005958.4. 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
	MTNR1A	NM_005958.4	MANE Select	c.160C>T	p.Arg54Trp	missense	Exon 1 of 2	NP_005949.1	P48039

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTNR1A	ENST00000307161.5	TSL:1 MANE Select	c.160C>T	p.Arg54Trp	missense	Exon 1 of 2	ENSP00000302811.5	P48039
ENSG00000272297	ENST00000509111.2	TSL:3	c.121C>T	p.Arg41Trp	missense	Exon 1 of 2	ENSP00000422449.2	H0Y8X5
MTNR1A	ENST00000703170.1		c.160C>T	p.Arg54Trp	missense	Exon 1 of 2	ENSP00000515216.1	P48039

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00833

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000532

AC:

116

AN:

217858

AF XY:

0.000534

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000315

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00612

Gnomad FIN exome

AF:

0.000108

Gnomad NFE exome

AF:

0.0000522

Gnomad OTH exome

AF:

0.000738

GnomAD4 exome

AF:

0.000726

AC:

1048

AN:

1443302

Hom.:

Cov.:

AF XY:

0.000744

AC XY:

533

AN XY:

716366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33178

American (AMR)

AF:

0.0000236

AC:

AN:

42454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25704

East Asian (EAS)

AF:

0.0242

AC:

942

AN:

38848

South Asian (SAS)

AF:

0.000204

AC:

AN:

83178

European-Finnish (FIN)

AF:

0.0000579

AC:

AN:

51828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4896

European-Non Finnish (NFE)

AF:

0.0000544

AC:

AN:

1103722

Other (OTH)

AF:

0.000420

AC:

AN:

59494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000328

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00835

AC:

AN:

5150

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68012

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000608

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000498

AC:

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.86

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.73

MutationAssessor

Pathogenic

3.4

PhyloP100

0.92

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.26

Sift

Uncertain

0.0020

Sift4G

Benign

0.16

Polyphen

1.0

Vest4

0.28

MVP

0.91

MPC

0.47

ClinPred

0.16

GERP RS

3.8

PromoterAI

-0.060

Neutral

(source)

Varity_R

0.54

gMVP

0.71

Mutation Taster

=77/23

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over