11-92981951-A-G

Position:

• chr11-92981951-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000257068.3(MTNR1B):​c.728A>G​(p.Lys243Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,614,164 control chromosomes in the GnomAD database, including 2,997 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).

• Frequency:
  • Genomes: 𝑓 0.087 (1227 hom., cov: 33)
  • Exomes 𝑓: 0.033 (1770 hom.)
• Consequence: MTNR1B ENST00000257068.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.170

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=0.00430429).
• BP6: Variant 11-92981951-A-G is Benign according to our data. Variant chr11-92981951-A-G is described in ClinVar as [Benign]. Clinvar id is 3060517.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTNR1B	NM_005959.5	c.728A>G	p.Lys243Arg	missense_variant	2/2	ENST00000257068.3	NP_005950.1
MTNR1B	XM_011542839.3	c.728A>G	p.Lys243Arg	missense_variant	2/3		XP_011541141.1
MTNR1B	XM_017017777.2	c.602A>G	p.Lys201Arg	missense_variant	2/3		XP_016873266.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTNR1B	ENST00000257068.3	c.728A>G	p.Lys243Arg	missense_variant	2/2	1	NM_005959.5	ENSP00000257068	P1
MTNR1B	ENST00000528076.1	c.166-2856A>G		intron_variant		3		ENSP00000433573
MTNR1B	ENST00000532482.1	c.*619A>G		3_prime_UTR_variant, NMD_transcript_variant	3/3	5		ENSP00000436101

Frequencies

GnomAD3 genomes AF: 0.0865 AC: 13168 AN: 152160 Hom.: 1225 Cov.: 33

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0736

GnomAD3 exomes AF: 0.0395 AC: 9930 AN: 251458 Hom.: 572 AF XY: 0.0351 AC XY: 4769 AN XY: 135908

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.0206

Gnomad ASJ exome AF: 0.0762

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0133

Gnomad FIN exome AF: 0.0292

Gnomad NFE exome AF: 0.0297

Gnomad OTH exome AF: 0.0327

GnomAD4 exome AF: 0.0326 AC: 47627 AN: 1461886 Hom.: 1770 Cov.: 31 AF XY: 0.0314 AC XY: 22853 AN XY: 727244

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.0229

Gnomad4 ASJ exome AF: 0.0766

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.0259

Gnomad4 NFE exome AF: 0.0278

Gnomad4 OTH exome AF: 0.0420

GnomAD4 genome AF: 0.0866 AC: 13185 AN: 152278 Hom.: 1227 Cov.: 33 AF XY: 0.0836 AC XY: 6226 AN XY: 74472

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.0375

Gnomad4 ASJ AF: 0.0801

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0272

Gnomad4 NFE AF: 0.0296

Gnomad4 OTH AF: 0.0728

Alfa AF: 0.0556 Hom.: 284

Bravo AF: 0.0947

TwinsUK AF: 0.0337 AC: 125

ALSPAC AF: 0.0288 AC: 111

ESP6500AA AF: 0.235 AC: 1033

ESP6500EA AF: 0.0330 AC: 284

ExAC AF: 0.0421 AC: 5116

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0347

EpiControl AF: 0.0294

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

Nov 06, 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	0.081
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.6
DANN	Benign	0.88
DEOGEN2	Benign	0.048	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.26	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.060
Sift	Benign	0.77	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.0030
MPC		0.13
ClinPred		0.000014	T
GERP RS		1.1
Varity_R		0.030
gMVP		0.14

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: rs61747139; hg19: chr11-92715117;