dbSNP rs28383653: MTNR1A:p.Gly166Glu (chr4-186534245-C-T) – 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.497G>A(p.Gly166Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,950 control chromosomes in the GnomAD database, including 187 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 0.0097 ( 14 hom., cov: 32)

Exomes 𝑓: 0.014 ( 173 hom. )

Consequence

MTNR1A
NM_005958.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.25

Publications

15 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=0.009611458).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0138 (20103/1461878) while in subpopulation NFE AF = 0.0162 (17968/1112004). AF 95% confidence interval is 0.016. There are 173 homozygotes in GnomAdExome4. There are 9752 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTNR1A	NM_005958.4 link	c.497G>A	p.Gly166Glu	missense_variant	Exon 2 of 2	ENST00000307161.5	NP_005949.1	P48039
MTNR1A	XM_011532002.4 link	c.242G>A	p.Gly81Glu	missense_variant	Exon 2 of 2		XP_011530304.1
LOC105377596	XR_007058498.1 link	n.143+9350C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTNR1A	ENST00000307161.5 link	c.497G>A	p.Gly166Glu	missense_variant	Exon 2 of 2	1	NM_005958.4	ENSP00000302811.5		P48039
ENSG00000272297	ENST00000509111.2 link	c.145+20937G>A		intron_variant	Intron 1 of 1	3		ENSP00000422449.2		H0Y8X5

Frequencies

GnomAD3 genomes

AF:

0.00968

AC:

1471

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.00815

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00463

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0149

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.00939

AC:

2360

AN:

251376

AF XY:

0.00944

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00708

Gnomad ASJ exome

AF:

0.0177

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00421

Gnomad NFE exome

AF:

0.0146

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0138

AC:

20103

AN:

1461878

Hom.:

173

Cov.:

AF XY:

0.0134

AC XY:

9752

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

33480

American (AMR)

AF:

0.00760

AC:

340

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0180

AC:

471

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00174

AC:

150

AN:

86256

European-Finnish (FIN)

AF:

0.00414

AC:

221

AN:

53418

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0162

AC:

17968

AN:

1112004

Other (OTH)

AF:

0.0141

AC:

853

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1327

2654

3980

5307

6634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

704

1408

2112

2816

3520

<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:

0.00968

AC:

1472

AN:

152072

Hom.:

Cov.:

AF XY:

0.00926

AC XY:

688

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00318

AC:

132

AN:

41498

American (AMR)

AF:

0.00820

AC:

125

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000623

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00463

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0149

AC:

1011

AN:

67982

Other (OTH)

AF:

0.0138

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

152

228

304

380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0128

Hom.:

Bravo

AF:

0.0110

TwinsUK

AF:

0.0181

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0162

AC:

139

ExAC

AF:

0.00945

AC:

1147

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0139

EpiControl

AF:

0.0168

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.8

PhyloP100

3.3

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.30

Sift

Benign

0.067

Sift4G

Benign

0.095

Polyphen

0.97

Vest4

0.35

MVP

0.91

MPC

0.35

ClinPred

0.080

GERP RS

4.1

Varity_R

0.54

gMVP

0.77

Mutation Taster

=79/21

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