11-92969946-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005959.5(MTNR1B):​c.221C>T​(p.Ala74Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,607,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MTNR1B
NM_005959.5 missense, splice_region

Scores

5
14
Splicing: ADA: 0.8561
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.50
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27915642).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTNR1BNM_005959.5 linkc.221C>T p.Ala74Val missense_variant, splice_region_variant Exon 1 of 2 ENST00000257068.3 NP_005950.1 P49286
MTNR1BXM_011542839.3 linkc.221C>T p.Ala74Val missense_variant, splice_region_variant Exon 1 of 3 XP_011541141.1 P49286

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTNR1BENST00000257068.3 linkc.221C>T p.Ala74Val missense_variant, splice_region_variant Exon 1 of 2 1 NM_005959.5 ENSP00000257068.2 P49286
MTNR1BENST00000528076.1 linkc.162C>T p.Arg54Arg splice_region_variant, synonymous_variant Exon 1 of 2 3 ENSP00000433573.1 H0YDG4
MTNR1BENST00000532482.1 linkn.221C>T splice_region_variant, non_coding_transcript_exon_variant Exon 1 of 3 5 ENSP00000436101.1 E9PR36

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000125
AC:
3
AN:
239052
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
130368
show subpopulations
Gnomad AFR exome
AF:
0.000133
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000554
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:
0.00000550
AC:
8
AN:
1455768
Hom.:
0
Cov.:
32
AF XY:
0.00000553
AC XY:
4
AN XY:
723556
show subpopulations
Gnomad4 AFR exome
AF:
0.000150
Gnomad4 AMR exome
AF:
0.00
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:
9.01e-7
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000227

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 16, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.221C>T (p.A74V) alteration is located in exon 1 (coding exon 1) of the MTNR1B gene. This alteration results from a C to T substitution at nucleotide position 221, causing the alanine (A) at amino acid position 74 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
0.22
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.48
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.28
T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.69
N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-2.0
N
REVEL
Benign
0.084
Sift
Benign
0.038
D
Sift4G
Benign
0.25
T
Polyphen
0.080
B
Vest4
0.24
MVP
0.81
MPC
0.19
ClinPred
0.19
T
GERP RS
4.1
Varity_R
0.27
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.86
dbscSNV1_RF
Benign
0.57
SpliceAI score (max)
0.48
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.48
Position offset: -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: rs1297993419; hg19: chr11-92703112; API