4-186555211-A-G

Position:

• chr4-186555211-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP4

The NM_005958.4(MTNR1A):​c.155T>C​(p.Val52Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,595,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (1 hom.)
• Consequence: MTNR1A NM_005958.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.55

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.31527254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTNR1A	NM_005958.4	c.155T>C	p.Val52Ala	missense_variant	1/2	ENST00000307161.5	NP_005949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTNR1A	ENST00000307161.5	c.155T>C	p.Val52Ala	missense_variant	1/2	1	NM_005958.4	ENSP00000302811	P1
MTNR1A	ENST00000703170.1	c.155T>C	p.Val52Ala	missense_variant	1/2			ENSP00000515216	P1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000589 AC: 128 AN: 217488 Hom.: 0 AF XY: 0.000629 AC XY: 74 AN XY: 117688

Gnomad AFR exome AF: 0.0000743

Gnomad AMR exome AF: 0.000126

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.000121

Gnomad SAS exome AF: 0.000738

Gnomad FIN exome AF: 0.000108

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.000371

GnomAD4 exome AF: 0.000884 AC: 1275 AN: 1442982 Hom.: 1 Cov.: 31 AF XY: 0.000884 AC XY: 633 AN XY: 716172

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000141

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000950

Gnomad4 FIN exome AF: 0.000193

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.000673

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74412

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000941 Hom.: 0

Bravo AF: 0.000620

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00117 AC: 10

ExAC AF: 0.000548 AC: 66

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.155T>C (p.V52A) alteration is located in exon 1 (coding exon 1) of the MTNR1A gene. This alteration results from a T to C substitution at nucleotide position 155, causing the valine (V) at amino acid position 52 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.010	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.056	T
Polyphen		1.0	D
Vest4		0.83
MVP		0.91
MPC		0.96
ClinPred		0.14	T
GERP RS		4.7
Varity_R		0.55
gMVP		0.75

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: rs144178215; hg19: chr4-187476365;