chr4-186533797-T-C

Variant names:

• chr4-186533797-T-C
• rs8192551
• NM_005958.4:c.945A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005958.4(MTNR1A):​c.945A>G​(p.Thr315Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0466 in 1,614,108 control chromosomes in the GnomAD database, including 2,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T315T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.059 (360 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1854 hom.)
• Consequence: MTNR1A NM_005958.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.315
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 4-186533797-T-C is Benign according to our data. Variant chr4-186533797-T-C is described in ClinVar as Benign. ClinVar VariationId is 1252210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.315 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005958.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTNR1A	NM_005958.4	MANE Select	c.945A>G	p.Thr315Thr	synonymous	Exon 2 of 2	NP_005949.1	P48039

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTNR1A	ENST00000307161.5	TSL:1 MANE Select	c.945A>G	p.Thr315Thr	synonymous	Exon 2 of 2	ENSP00000302811.5	P48039
	ENSG00000272297	ENST00000509111.2	TSL:3	c.145+21385A>G		intron	N/A	ENSP00000422449.2	H0Y8X5
	MTNR1A	ENST00000703170.1		c.945A>G	p.Thr315Thr	synonymous	Exon 2 of 2	ENSP00000515216.1	P48039

Frequencies

GnomAD3 genomes AF: 0.0593 AC: 9021 AN: 152152 Hom.: 353 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.0790

Gnomad SAS AF: 0.0380

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0433

Gnomad OTH AF: 0.0588

GnomAD2 exomes AF: 0.0422 AC: 10609 AN: 251494 AF XY: 0.0418

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.0253

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.0785

Gnomad FIN exome AF: 0.00661

Gnomad NFE exome AF: 0.0415

Gnomad OTH exome AF: 0.0436

GnomAD4 exome AF: 0.0453 AC: 66166 AN: 1461838 Hom.: 1854 Cov.: 32 AF XY: 0.0451 AC XY: 32798 AN XY: 727210

African (AFR) AF: 0.105 AC: 3511 AN: 33480

American (AMR) AF: 0.0279 AC: 1246 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 565 AN: 26136

East Asian (EAS) AF: 0.0939 AC: 3726 AN: 39698

South Asian (SAS) AF: 0.0399 AC: 3439 AN: 86258

European-Finnish (FIN) AF: 0.00760 AC: 406 AN: 53420

Middle Eastern (MID) AF: 0.0472 AC: 272 AN: 5766

European-Non Finnish (NFE) AF: 0.0448 AC: 49827 AN: 1111960

Other (OTH) AF: 0.0526 AC: 3174 AN: 60396

GnomAD4 genome AF: 0.0594 AC: 9047 AN: 152270 Hom.: 360 Cov.: 32 AF XY: 0.0565 AC XY: 4204 AN XY: 74454

African (AFR) AF: 0.109 AC: 4516 AN: 41532

American (AMR) AF: 0.0454 AC: 694 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.0790 AC: 410 AN: 5188

South Asian (SAS) AF: 0.0384 AC: 185 AN: 4816

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10618

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0433 AC: 2943 AN: 68026

Other (OTH) AF: 0.0577 AC: 122 AN: 2114

Alfa AF: 0.0402 Hom.: 86

Bravo AF: 0.0648

Asia WGS AF: 0.0590 AC: 206 AN: 3478

EpiCase AF: 0.0489

EpiControl AF: 0.0456

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.5
DANN	Benign	0.29
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8192551; hg19: chr4-187454951; COSMIC: COSV56156421;