Genetic Variant NM_005958.4:c.337G>A (chr4-186534405-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005958.4(MTNR1A):c.337G>A(p.Gly113Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

MTNR1A
NM_005958.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.259763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTNR1A	NM_005958.4 link	c.337G>A	p.Gly113Ser	missense_variant	Exon 2 of 2	ENST00000307161.5	NP_005949.1	P48039
MTNR1A	XM_011532002.4 link	c.82G>A	p.Gly28Ser	missense_variant	Exon 2 of 2		XP_011530304.1
LOC105377596	XR_007058498.1 link	n.143+9510C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MTNR1A	ENST00000307161.5 link	c.337G>A	p.Gly113Ser	missense_variant	Exon 2 of 2	1	NM_005958.4	ENSP00000302811.5	P48039
ENSG00000272297	ENST00000509111.2 link	c.145+20777G>A		intron_variant	Intron 1 of 1	3		ENSP00000422449.2	H0Y8X5
MTNR1A	ENST00000703170.1 link	c.337G>A	p.Gly113Ser	missense_variant	Exon 2 of 2			ENSP00000515216.1	P48039

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251436

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.337G>A (p.G113S) alteration is located in exon 2 (coding exon 2) of the MTNR1A gene. This alteration results from a G to A substitution at nucleotide position 337, causing the glycine (G) at amino acid position 113 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.012

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.88

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.26

Sift

Benign

0.086

Sift4G

Benign

0.17

Polyphen

0.81

Vest4

0.30

MVP

0.96

MPC

0.31

ClinPred

0.11

GERP RS

4.5

Varity_R

0.56

gMVP

0.69

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over