rs8192552

Positions:

• chr11-92969796-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
MTNR1B	NM_005959.5	c.71G>A	p.Gly24Glu	missense_variant	1/2	ENST00000257068.3	NP_005950.1
MTNR1B	XM_011542839.3	c.71G>A	p.Gly24Glu	missense_variant	1/3		XP_011541141.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTNR1B	ENST00000257068.3	c.71G>A	p.Gly24Glu	missense_variant	1/2	1	NM_005959.5	ENSP00000257068	P1
MTNR1B	ENST00000528076.1	c.15G>A	p.Gly5=	synonymous_variant	1/2	3		ENSP00000433573
MTNR1B	ENST00000532482.1	c.71G>A	p.Gly24Glu	missense_variant, NMD_transcript_variant	1/3	5		ENSP00000436101

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: no assertion criteria provided

Submissions by phenotype

MTNR1B-related disorder Benign:1

Benign, no assertion criteria provided

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;