chr4-186533709-C-T

Position:

• chr4-186533709-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000307161.5(MTNR1A):​c.1033G>A​(p.Val345Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,614,060 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: MTNR1A ENST00000307161.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.273

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011804044).
• BP6: Variant 4-186533709-C-T is Benign according to our data. Variant chr4-186533709-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2357305.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTNR1A	NM_005958.4	c.1033G>A	p.Val345Ile	missense_variant	2/2	ENST00000307161.5	NP_005949.1
LOC105377596	XR_007058498.1	n.143+8814C>T		intron_variant, non_coding_transcript_variant
MTNR1A	XM_011532002.4	c.778G>A	p.Val260Ile	missense_variant	2/2		XP_011530304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTNR1A	ENST00000307161.5	c.1033G>A	p.Val345Ile	missense_variant	2/2	1	NM_005958.4	ENSP00000302811	P1
MTNR1A	ENST00000703170.1	c.1033G>A	p.Val345Ile	missense_variant	2/2			ENSP00000515216	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000306 AC: 77 AN: 251480 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1461864 Hom.: 1 Cov.: 32 AF XY: 0.000165 AC XY: 120 AN XY: 727230

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74348

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.013
DANN	Benign	0.84
DEOGEN2	Benign	0.084	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.94	D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.050
Sift	Benign	0.41	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.053
MVP		0.48
MPC		0.21
ClinPred		0.018	T
GERP RS		-4.4
Varity_R		0.022
gMVP		0.26

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: rs200192631; hg19: chr4-187454863;