11-92969811-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_005959.5(MTNR1B):c.86G>A(p.Arg29Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,416,846 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MTNR1B NM_005959.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.837

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048462957).
• BP6: Variant 11-92969811-G-A is Benign according to our data. Variant chr11-92969811-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3216985.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTNR1B	NM_005959.5	c.86G>A	p.Arg29Gln	missense_variant	1/2	ENST00000257068.3
MTNR1B	XM_011542839.3	c.86G>A	p.Arg29Gln	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTNR1B	ENST00000257068.3	c.86G>A	p.Arg29Gln	missense_variant	1/2	1	NM_005959.5	P1
MTNR1B	ENST00000528076.1	c.30G>A	p.Ala10=	synonymous_variant	1/2	3
MTNR1B	ENST00000532482.1	c.86G>A	p.Arg29Gln	missense_variant, NMD_transcript_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000246 AC: 5 AN: 203530 Hom.: 0 AF XY: 0.0000178 AC XY: 2 AN XY: 112308

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000677

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000326

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000176 AC: 25 AN: 1416846 Hom.: 0 Cov.: 32 AF XY: 0.0000157 AC XY: 11 AN XY: 702098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000971

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.0000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.60
Dann	Benign	0.84
DEOGEN2	Benign	0.038	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.49	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.041
Sift	Benign	0.59	T
Sift4G	Benign	0.63	T
Polyphen		0.0030	B
Vest4		0.11
MutPred		0.35		Loss of MoRF binding (P = 0.0289);
MVP		0.35
MPC		0.18
ClinPred		0.031	T
GERP RS		-8.4
Varity_R		0.022
gMVP		0.31

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: rs1565177580; hg19: chr11-92702977;