11-92981824-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005959.5(MTNR1B):c.601A>G(p.Thr201Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MTNR1B NM_005959.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.65

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTNR1B	NM_005959.5	c.601A>G	p.Thr201Ala	missense_variant	2/2	ENST00000257068.3
MTNR1B	XM_011542839.3	c.601A>G	p.Thr201Ala	missense_variant	2/3
MTNR1B	XM_017017777.2	c.475A>G	p.Thr159Ala	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTNR1B	ENST00000257068.3	c.601A>G	p.Thr201Ala	missense_variant	2/2	1	NM_005959.5	P1
MTNR1B	ENST00000528076.1	c.166-2983A>G		intron_variant		3
MTNR1B	ENST00000532482.1	c.*492A>G		3_prime_UTR_variant, NMD_transcript_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2024

The c.601A>G (p.T201A) alteration is located in exon 2 (coding exon 2) of the MTNR1B gene. This alteration results from a A to G substitution at nucleotide position 601, causing the threonine (T) at amino acid position 201 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Benign	0.86
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0056	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.29
Sift	Benign	0.062	T
Sift4G	Benign	0.20	T
Polyphen		0.97	D
Vest4		0.49
MutPred		0.60		Loss of glycosylation at T201 (P = 0.0947);
MVP		0.63
MPC		0.43
ClinPred		0.87	D
GERP RS		1.9
Varity_R		0.19
gMVP		0.28

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: rs1347849879; hg19: chr11-92714990;