Genetic Variant MTNR1B:p.Ile142Val (chr11-92981647-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005959.5(MTNR1B):c.424A>G(p.Ile142Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MTNR1B
NM_005959.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.22

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTNR1B	NM_005959.5 link	c.424A>G	p.Ile142Val	missense_variant	Exon 2 of 2	ENST00000257068.3	NP_005950.1	P49286
MTNR1B	XM_011542839.3 link	c.424A>G	p.Ile142Val	missense_variant	Exon 2 of 3		XP_011541141.1	P49286
MTNR1B	XM_017017777.2 link	c.298A>G	p.Ile100Val	missense_variant	Exon 2 of 3		XP_016873266.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MTNR1B	ENST00000257068.3 link	c.424A>G	p.Ile142Val	missense_variant	Exon 2 of 2	1	NM_005959.5	ENSP00000257068.2	P49286
MTNR1B	ENST00000528076.1 link	c.165-3160A>G		intron_variant	Intron 1 of 1	3		ENSP00000433573.1	H0YDG4
MTNR1B	ENST00000532482.1 link	n.*315A>G		non_coding_transcript_exon_variant	Exon 3 of 3	5		ENSP00000436101.1	E9PR36
MTNR1B	ENST00000532482.1 link	n.*315A>G		3_prime_UTR_variant	Exon 3 of 3	5		ENSP00000436101.1	E9PR36

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251448

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.424A>G (p.I142V) alteration is located in exon 2 (coding exon 2) of the MTNR1B gene. This alteration results from a A to G substitution at nucleotide position 424, causing the isoleucine (I) at amino acid position 142 to be replaced by a valine (V). 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

0.24

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.37

CADD

Benign

8.2

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.0078

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.77

REVEL

Benign

0.22

Sift

Benign

0.067

Sift4G

Benign

0.20

Polyphen

0.34

Vest4

0.13

MutPred

0.59

Gain of MoRF binding (P = 0.2221);

MVP

0.75

MPC

0.34

ClinPred

0.30

GERP RS

0.32

Varity_R

0.11

gMVP

0.18

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