rs8192552

Variant names:

• chr11-92969796-G-A
• rs8192552
• NM_005959.5:c.71G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• 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
• Publications: 26 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005959.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTNR1B	NM_005959.5	MANE Select	c.71G>A	p.Gly24Glu	missense	Exon 1 of 2	NP_005950.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTNR1B	ENST00000257068.3	TSL:1 MANE Select	c.71G>A	p.Gly24Glu	missense	Exon 1 of 2	ENSP00000257068.2
	MTNR1B	ENST00000528076.1	TSL:3	c.12G>A	p.Gly4Gly	synonymous	Exon 1 of 2	ENSP00000433573.1
	MTNR1B	ENST00000532482.1	TSL:5	n.71G>A		non_coding_transcript_exon	Exon 1 of 3	ENSP00000436101.1

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

GnomAD2 exomes AF: 0.0678 AC: 13499 AN: 199106 AF XY: 0.0696

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 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

African (AFR) AF: 0.0957 AC: 2919 AN: 30494

American (AMR) AF: 0.0455 AC: 1842 AN: 40482

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 851 AN: 24498

East Asian (EAS) AF: 0.00815 AC: 296 AN: 36328

South Asian (SAS) AF: 0.0878 AC: 7077 AN: 80560

European-Finnish (FIN) AF: 0.0432 AC: 2054 AN: 47558

Middle Eastern (MID) AF: 0.0602 AC: 320 AN: 5312

European-Non Finnish (NFE) AF: 0.0839 AC: 90863 AN: 1083130

Other (OTH) AF: 0.0709 AC: 4085 AN: 57648

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

African (AFR) AF: 0.0937 AC: 3893 AN: 41534

American (AMR) AF: 0.0446 AC: 682 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3470

East Asian (EAS) AF: 0.00447 AC: 23 AN: 5144

South Asian (SAS) AF: 0.0861 AC: 416 AN: 4832

European-Finnish (FIN) AF: 0.0384 AC: 407 AN: 10602

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0795 AC: 5405 AN: 67980

Other (OTH) AF: 0.0621 AC: 131 AN: 2108

Alfa AF: 0.0733 Hom.: 233

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

Oct 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

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
PhyloP100		1.2
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
PromoterAI		0.012	Neutral
Varity_R		0.040
gMVP		0.69
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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