rs7654853

Variant names:

• chr4-186534107-A-G
• rs7654853
• NM_005958.4:c.635T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-186534107-A-G
• chr4-186534107-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005958.4(MTNR1A):​c.635T>C​(p.Ile212Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00328 in 1,614,154 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (74 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (60 hom.)
• Consequence: MTNR1A NM_005958.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.03
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008351803).
• BP6: Variant 4-186534107-A-G is Benign according to our data. Variant chr4-186534107-A-G is described in ClinVar as Benign. ClinVar VariationId is 791529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0613 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.635T>C	p.Ile212Thr	missense	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.635T>C	p.Ile212Thr	missense	Exon 2 of 2	ENSP00000302811.5	P48039
	ENSG00000272297	ENST00000509111.2	TSL:3	c.145+21075T>C		intron	N/A	ENSP00000422449.2	H0Y8X5
	MTNR1A	ENST00000703170.1		c.635T>C	p.Ile212Thr	missense	Exon 2 of 2	ENSP00000515216.1	P48039

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2776 AN: 152166 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.0634

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00465 AC: 1167 AN: 251224 AF XY: 0.00340

Gnomad AFR exome AF: 0.0651

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00172 AC: 2511 AN: 1461870 Hom.: 60 Cov.: 32 AF XY: 0.00149 AC XY: 1082 AN XY: 727234

African (AFR) AF: 0.0619 AC: 2072 AN: 33480

American (AMR) AF: 0.00277 AC: 124 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1112002

Other (OTH) AF: 0.00386 AC: 233 AN: 60396

GnomAD4 genome AF: 0.0182 AC: 2779 AN: 152284 Hom.: 74 Cov.: 32 AF XY: 0.0176 AC XY: 1310 AN XY: 74468

African (AFR) AF: 0.0633 AC: 2629 AN: 41554

American (AMR) AF: 0.00680 AC: 104 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68022

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.00755 Hom.: 64

Bravo AF: 0.0206

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0676 AC: 298

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00605 AC: 734

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.0
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.082
Sift	Benign	0.19	T
Sift4G	Benign	0.43	T
Polyphen		0.0060	B
Vest4		0.63
MVP		0.76
MPC		0.33
ClinPred		0.039	T
GERP RS		2.3
Varity_R		0.13
gMVP		0.49
Mutation Taster		=78/22	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: rs7654853; hg19: chr4-187455261;