4-186534272-G-A

Position:

• chr4-186534272-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005958.4(MTNR1A):​c.470C>T​(p.Ala157Val) variant causes a missense change. The variant allele was found at a frequency of 0.000865 in 1,614,142 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (19 hom.)
• Consequence: MTNR1A NM_005958.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.66

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]

LOC105377596 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008299112).
• BP6: Variant 4-186534272-G-A is Benign according to our data. Variant chr4-186534272-G-A is described in ClinVar as [Benign]. Clinvar id is 716546.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000946 (144/152262) while in subpopulation EAS AF= 0.0209 (108/5168). AF 95% confidence interval is 0.0177. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTNR1A	NM_005958.4	c.470C>T	p.Ala157Val	missense_variant	2/2	ENST00000307161.5	NP_005949.1
LOC105377596	XR_007058498.1	n.143+9377G>A		intron_variant, non_coding_transcript_variant
MTNR1A	XM_011532002.4	c.215C>T	p.Ala72Val	missense_variant	2/2		XP_011530304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTNR1A	ENST00000307161.5	c.470C>T	p.Ala157Val	missense_variant	2/2	1	NM_005958.4	ENSP00000302811	P1
MTNR1A	ENST00000703170.1	c.470C>T	p.Ala157Val	missense_variant	2/2			ENSP00000515216	P1

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0210

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00211 AC: 531 AN: 251364 Hom.: 1 AF XY: 0.00167 AC XY: 227 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0198

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000856 AC: 1252 AN: 1461880 Hom.: 19 Cov.: 33 AF XY: 0.000800 AC XY: 582 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0251

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000946 AC: 144 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74444

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0209

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000767 Hom.: 0

Bravo AF: 0.000929

ExAC AF: 0.00184 AC: 223

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.31
DANN	Benign	0.34
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.21	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.085
Sift	Benign	0.67	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.088
MVP		0.22
MPC		0.26
ClinPred		0.0080	T
GERP RS		-0.62
Varity_R		0.024
gMVP		0.22

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: rs1800884; hg19: chr4-187455426; COSMIC: COSV56156902;