rs8192550

Variant names:

• chr4-186533818-T-C
• rs8192550
• NM_005958.4:c.924A>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.924A>G​(p.Arg308Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,614,016 control chromosomes in the GnomAD database, including 1,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (96 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1516 hom.)
• Consequence: MTNR1A NM_005958.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.321
• Publications: 7 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=-0.82).
• BP6: Variant 4-186533818-T-C is Benign according to our data. Variant chr4-186533818-T-C is described in ClinVar as Benign. ClinVar VariationId is 1250542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.321 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0639 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.924A>G	p.Arg308Arg	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.924A>G	p.Arg308Arg	synonymous	Exon 2 of 2	ENSP00000302811.5	P48039
	ENSG00000272297	ENST00000509111.2	TSL:3	c.145+21364A>G		intron	N/A	ENSP00000422449.2	H0Y8X5
	MTNR1A	ENST00000703170.1		c.924A>G	p.Arg308Arg	synonymous	Exon 2 of 2	ENSP00000515216.1	P48039

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4451 AN: 152068 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.00819

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.0699

Gnomad SAS AF: 0.0326

Gnomad FIN AF: 0.00547

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0427

Gnomad OTH AF: 0.0341

GnomAD2 exomes AF: 0.0332 AC: 8344 AN: 251494 AF XY: 0.0347

Gnomad AFR exome AF: 0.00726

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.0724

Gnomad FIN exome AF: 0.00647

Gnomad NFE exome AF: 0.0411

Gnomad OTH exome AF: 0.0358

GnomAD4 exome AF: 0.0412 AC: 60262 AN: 1461830 Hom.: 1516 Cov.: 32 AF XY: 0.0413 AC XY: 30038 AN XY: 727204

African (AFR) AF: 0.00684 AC: 229 AN: 33478

American (AMR) AF: 0.0203 AC: 908 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 559 AN: 26136

East Asian (EAS) AF: 0.0697 AC: 2767 AN: 39698

South Asian (SAS) AF: 0.0349 AC: 3010 AN: 86258

European-Finnish (FIN) AF: 0.00745 AC: 398 AN: 53420

Middle Eastern (MID) AF: 0.0397 AC: 229 AN: 5768

European-Non Finnish (NFE) AF: 0.0445 AC: 49531 AN: 1111952

Other (OTH) AF: 0.0436 AC: 2631 AN: 60396

GnomAD4 genome AF: 0.0292 AC: 4446 AN: 152186 Hom.: 96 Cov.: 32 AF XY: 0.0275 AC XY: 2047 AN XY: 74390

African (AFR) AF: 0.00817 AC: 339 AN: 41490

American (AMR) AF: 0.0289 AC: 442 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.0699 AC: 362 AN: 5182

South Asian (SAS) AF: 0.0331 AC: 159 AN: 4806

European-Finnish (FIN) AF: 0.00547 AC: 58 AN: 10612

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0427 AC: 2903 AN: 68030

Other (OTH) AF: 0.0332 AC: 70 AN: 2106

Alfa AF: 0.0353 Hom.: 69

Bravo AF: 0.0303

Asia WGS AF: 0.0410 AC: 142 AN: 3478

EpiCase AF: 0.0482

EpiControl AF: 0.0455

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	-0.82
CADD	Benign	1.9
DANN	Benign	0.44
PhyloP100		0.32
Mutation Taster		=99/1	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: rs8192550; hg19: chr4-187454972; COSMIC: COSV56156431;