chr4-186534245-C-T

Position:

• chr4-186534245-C-T

Variant summary

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

The NM_005958.4(MTNR1A):​c.497G>A​(p.Gly166Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,950 control chromosomes in the GnomAD database, including 187 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.

• Frequency:
  • Genomes: 𝑓 0.0097 (14 hom., cov: 32)
  • Exomes 𝑓: 0.014 (173 hom.)
• Consequence: MTNR1A NM_005958.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.25

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=0.009611458).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0138 (20103/1461878) while in subpopulation NFE AF= 0.0162 (17968/1112004). AF 95% confidence interval is 0.016. There are 173 homozygotes in gnomad4_exome. There are 9752 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTNR1A	NM_005958.4	c.497G>A	p.Gly166Glu	missense_variant	2/2	ENST00000307161.5	NP_005949.1
MTNR1A	XM_011532002.4	c.242G>A	p.Gly81Glu	missense_variant	2/2		XP_011530304.1
LOC105377596	XR_007058498.1	n.143+9350C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTNR1A	ENST00000307161.5	c.497G>A	p.Gly166Glu	missense_variant	2/2	1	NM_005958.4	ENSP00000302811.5
ENSG00000272297	ENST00000509111.2	c.145+20937G>A		intron_variant		3		ENSP00000422449.2
MTNR1A	ENST00000703170.1	c.497G>A	p.Gly166Glu	missense_variant	2/2			ENSP00000515216.1

Frequencies

GnomAD3 genomes AF: 0.00968 AC: 1471 AN: 151952 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.00815

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00463

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00939 AC: 2360 AN: 251376 Hom.: 21 AF XY: 0.00944 AC XY: 1283 AN XY: 135874

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00708

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00421

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0138 AC: 20103 AN: 1461878 Hom.: 173 Cov.: 33 AF XY: 0.0134 AC XY: 9752 AN XY: 727240

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.00760

Gnomad4 ASJ exome AF: 0.0180

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00174

Gnomad4 FIN exome AF: 0.00414

Gnomad4 NFE exome AF: 0.0162

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.00968 AC: 1472 AN: 152072 Hom.: 14 Cov.: 32 AF XY: 0.00926 AC XY: 688 AN XY: 74328

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.00820

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00463

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.0138

Alfa AF: 0.0139 Hom.: 30

Bravo AF: 0.0110

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0162 AC: 139

ExAC AF: 0.00945 AC: 1147

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0139

EpiControl AF: 0.0168

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.30
Sift	Benign	0.067	T
Sift4G	Benign	0.095	T
Polyphen		0.97	D
Vest4		0.35
MVP		0.91
MPC		0.35
ClinPred		0.080	T
GERP RS		4.1
Varity_R		0.54
gMVP		0.77

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: rs28383653; hg19: chr4-187455399; COSMIC: COSV99048042;