chr4-186555211-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP4

The NM_005958.4(MTNR1A):ā€‹c.155T>Cā€‹(p.Val52Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,595,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00053 ( 0 hom., cov: 32)
Exomes š‘“: 0.00088 ( 1 hom. )

Consequence

MTNR1A
NM_005958.4 missense

Scores

5
10
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.55
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]

Genome browser will be placed here

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;
PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.31527254).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MTNR1ANM_005958.4 linkuse as main transcriptc.155T>C p.Val52Ala missense_variant 1/2 ENST00000307161.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MTNR1AENST00000307161.5 linkuse as main transcriptc.155T>C p.Val52Ala missense_variant 1/21 NM_005958.4 P1
MTNR1AENST00000703170.1 linkuse as main transcriptc.155T>C p.Val52Ala missense_variant 1/2 P1

Frequencies

GnomAD3 genomes
AF:
0.000533
AC:
81
AN:
152084
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000956
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000589
AC:
128
AN:
217488
Hom.:
0
AF XY:
0.000629
AC XY:
74
AN XY:
117688
show subpopulations
Gnomad AFR exome
AF:
0.0000743
Gnomad AMR exome
AF:
0.000126
Gnomad ASJ exome
AF:
0.000107
Gnomad EAS exome
AF:
0.000121
Gnomad SAS exome
AF:
0.000738
Gnomad FIN exome
AF:
0.000108
Gnomad NFE exome
AF:
0.00101
Gnomad OTH exome
AF:
0.000371
GnomAD4 exome
AF:
0.000884
AC:
1275
AN:
1442982
Hom.:
1
Cov.:
31
AF XY:
0.000884
AC XY:
633
AN XY:
716172
show subpopulations
Gnomad4 AFR exome
AF:
0.000121
Gnomad4 AMR exome
AF:
0.000141
Gnomad4 ASJ exome
AF:
0.0000389
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000950
Gnomad4 FIN exome
AF:
0.000193
Gnomad4 NFE exome
AF:
0.00102
Gnomad4 OTH exome
AF:
0.000673
GnomAD4 genome
AF:
0.000532
AC:
81
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.000430
AC XY:
32
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.000956
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000941
Hom.:
0
Bravo
AF:
0.000620
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00117
AC:
10
ExAC
AF:
0.000548
AC:
66
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 29, 2022The c.155T>C (p.V52A) alteration is located in exon 1 (coding exon 1) of the MTNR1A gene. This alteration results from a T to C substitution at nucleotide position 155, causing the valine (V) at amino acid position 52 to be replaced by an alanine (A). 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
Pathogenic
0.89
BayesDel_addAF
Benign
-0.018
T
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.32
T
MetaSVM
Uncertain
0.010
D
MutationAssessor
Pathogenic
3.3
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-2.5
D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.056
T
Polyphen
1.0
D
Vest4
0.83
MVP
0.91
MPC
0.96
ClinPred
0.14
T
GERP RS
4.7
Varity_R
0.55
gMVP
0.75

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.

Other links and lift over

dbSNP: rs144178215; hg19: chr4-187476365; API