rs1800885

Positions:

• chr4-186555206-G-A
• chr4-186555206-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005958.4(MTNR1A):​c.160C>T​(p.Arg54Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,595,554 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (23 hom.)
• Consequence: MTNR1A NM_005958.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.917

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010698348).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000726 (1048/1443302) while in subpopulation EAS AF= 0.0242 (942/38848). AF 95% confidence interval is 0.023. There are 23 homozygotes in gnomad4_exome. There are 533 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTNR1A	NM_005958.4	c.160C>T	p.Arg54Trp	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.160C>T	p.Arg54Trp	missense_variant	1/2	1	NM_005958.4	ENSP00000302811.5
ENSG00000272297	ENST00000509111.2	c.121C>T	p.Arg41Trp	missense_variant	1/2	3		ENSP00000422449.2
MTNR1A	ENST00000703170.1	c.160C>T	p.Arg54Trp	missense_variant	1/2			ENSP00000515216.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00833

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000532 AC: 116 AN: 217858 Hom.: 1 AF XY: 0.000534 AC XY: 63 AN XY: 117908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000315

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00612

Gnomad SAS exome AF: 0.000111

Gnomad FIN exome AF: 0.000108

Gnomad NFE exome AF: 0.0000522

Gnomad OTH exome AF: 0.000738

GnomAD4 exome AF: 0.000726 AC: 1048 AN: 1443302 Hom.: 23 Cov.: 31 AF XY: 0.000744 AC XY: 533 AN XY: 716366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0242

Gnomad4 SAS exome AF: 0.000204

Gnomad4 FIN exome AF: 0.0000579

Gnomad4 NFE exome AF: 0.0000544

Gnomad4 OTH exome AF: 0.000420

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74438

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00835

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000521 Hom.: 2

Bravo AF: 0.000117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000498 AC: 60

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.28
MVP		0.91
MPC		0.47
ClinPred		0.16	T
GERP RS		3.8
Varity_R		0.54
gMVP		0.71

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: rs1800885; hg19: chr4-187476360;