11-92969796-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005959.5(MTNR1B):c.71G>A(p.Gly24Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0779 in 1,558,178 control chromosomes in the GnomAD database, including 5,228 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.073 (496 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4732 hom.)
• Consequence: MTNR1B NM_005959.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.19

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018808544).
• BP6: Variant 11-92969796-G-A is Benign according to our data. Variant chr11-92969796-G-A is described in ClinVar as [Benign]. Clinvar id is 3058891.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTNR1B	NM_005959.5	c.71G>A	p.Gly24Glu	missense_variant	1/2	ENST00000257068.3
MTNR1B	XM_011542839.3	c.71G>A	p.Gly24Glu	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTNR1B	ENST00000257068.3	c.71G>A	p.Gly24Glu	missense_variant	1/2	1	NM_005959.5	P1
MTNR1B	ENST00000528076.1	c.15G>A	p.Gly5=	synonymous_variant	1/2	3
MTNR1B	ENST00000532482.1	c.71G>A	p.Gly24Glu	missense_variant, NMD_transcript_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.0729 AC: 11083 AN: 152050 Hom.: 495 Cov.: 32

Gnomad AFR AF: 0.0936

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0447

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00446

Gnomad SAS AF: 0.0862

Gnomad FIN AF: 0.0384

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0795

Gnomad OTH AF: 0.0628

GnomAD3 exomes AF: 0.0678 AC: 13499 AN: 199106 Hom.: 572 AF XY: 0.0696 AC XY: 7668 AN XY: 110164

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0451

Gnomad ASJ exome AF: 0.0366

Gnomad EAS exome AF: 0.00442

Gnomad SAS exome AF: 0.0923

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0819

Gnomad OTH exome AF: 0.0701

GnomAD4 exome AF: 0.0785 AC: 110307 AN: 1406010 Hom.: 4732 Cov.: 32 AF XY: 0.0784 AC XY: 54593 AN XY: 696396

Gnomad4 AFR exome AF: 0.0957

Gnomad4 AMR exome AF: 0.0455

Gnomad4 ASJ exome AF: 0.0347

Gnomad4 EAS exome AF: 0.00815

Gnomad4 SAS exome AF: 0.0878

Gnomad4 FIN exome AF: 0.0432

Gnomad4 NFE exome AF: 0.0839

Gnomad4 OTH exome AF: 0.0709

GnomAD4 genome AF: 0.0729 AC: 11093 AN: 152168 Hom.: 496 Cov.: 32 AF XY: 0.0700 AC XY: 5209 AN XY: 74394

Gnomad4 AFR AF: 0.0937

Gnomad4 AMR AF: 0.0446

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.00447

Gnomad4 SAS AF: 0.0861

Gnomad4 FIN AF: 0.0384

Gnomad4 NFE AF: 0.0795

Gnomad4 OTH AF: 0.0621

Alfa AF: 0.0750 Hom.: 184

Bravo AF: 0.0736

TwinsUK AF: 0.0828 AC: 307

ALSPAC AF: 0.0820 AC: 316

ESP6500AA AF: 0.0770 AC: 330

ESP6500EA AF: 0.0711 AC: 595

ExAC AF: 0.0668 AC: 7912

Asia WGS AF: 0.0480 AC: 166 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MTNR1B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	10
Dann	Benign	0.85
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.095
Sift	Benign	0.40	T
Sift4G	Uncertain	0.040	D
Polyphen		0.0040	B
Vest4		0.085
MPC		0.21
ClinPred		0.0044	T
GERP RS		0.12
Varity_R		0.040
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

Other links and lift over

dbSNP: rs8192552; hg19: chr11-92702962; COSMIC: COSV57065943; COSMIC: COSV57065943;