4-186555208-T-C

Position:

• chr4-186555208-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005958.4(MTNR1A):​c.158A>G​(p.Tyr53Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MTNR1A NM_005958.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0520

Genes affected

MTNR1A (HGNC:7463): (melatonin receptor 1A) This gene encodes one of two high affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This receptor is a G-protein coupled, 7-transmembrane receptor that is responsible for melatonin effects on mammalian circadian rhythm and reproductive alterations affected by day length. The receptor is an integral membrane protein that is readily detectable and localized to two specific regions of the brain. The hypothalamic suprachiasmatic nucleus appears to be involved in circadian rhythm while the hypophysial pars tuberalis may be responsible for the reproductive effects of melatonin. [provided by RefSeq, Jul 2008]

ENSG00000272297 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.357144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTNR1A	NM_005958.4	c.158A>G	p.Tyr53Cys	missense_variant	1/2	ENST00000307161.5	NP_005949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTNR1A	ENST00000307161.5	c.158A>G	p.Tyr53Cys	missense_variant	1/2	1	NM_005958.4	ENSP00000302811.5
ENSG00000272297	ENST00000509111.2	c.119A>G	p.Tyr40Cys	missense_variant	1/2	3		ENSP00000422449.2
MTNR1A	ENST00000703170.1	c.158A>G	p.Tyr53Cys	missense_variant	1/2			ENSP00000515216.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1443236 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716280

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Sep 04, 2024

The c.158A>G (p.Y53C) alteration is located in exon 1 (coding exon 1) of the MTNR1A gene. This alteration results from a A to G substitution at nucleotide position 158, causing the tyrosine (Y) at amino acid position 53 to be replaced by a cysteine (C). 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	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.042
Eigen_PC	Benign	-0.088
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Benign	0.033	D
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.29
MutPred		0.64		Gain of methylation at K56 (P = 0.0499);
MVP		0.84
MPC		0.40
ClinPred		0.46	T
GERP RS		1.9
Varity_R		0.12
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-187476362;