Genetic Variant ENST00000381433:c.-198G>A (chr22-40679455-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The ENST00000381433(MCHR1):c.-198G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

MCHR1
ENST00000381433 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.423

Variant links:

Genes affected

MCHR1 (HGNC:4479): (melanin concentrating hormone receptor 1) The protein encoded by this gene, a member of the G protein-coupled receptor family 1, is an integral plasma membrane protein which binds melanin-concentrating hormone. The encoded protein can inhibit cAMP accumulation and stimulate intracellular calcium flux, and is probably involved in the neuronal regulation of food consumption. Although structurally similar to somatostatin receptors, this protein does not seem to bind somatostatin. [provided by RefSeq, Jul 2008]

MCHR1 links:

ENSG00000289292 (HGNC:):

ENSG00000289292 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09420934).

BP6

Variant 22-40679455-G-A is Benign according to our data. Variant chr22-40679455-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3544136.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
LOC124905123	XR_007068109.1 link	n.4323+1153C>T	intron_variant	Intron 1 of 1
LOC124905123	XR_007068110.1 link	n.358+1153C>T	intron_variant	Intron 2 of 2
MCHR1	NM_005297.4 link	c.-198G>A	upstream_gene_variant		ENST00000249016.5	NP_005288.4	Q99705

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MCHR1	ENST00000381433 link	c.-198G>A	5_prime_UTR_variant	Exon 1 of 3	1		ENSP00000370841.3	A6ZJ87
MCHR1	ENST00000498400.1 link	n.132+51G>A	intron_variant	Intron 1 of 1	1
ENSG00000289292	ENST00000688408.2 link	n.367+1153C>T	intron_variant	Intron 2 of 2
MCHR1	ENST00000249016.5 link	c.-198G>A	upstream_gene_variant		1	NM_005297.4	ENSP00000249016.5	Q99705

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 26, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.19

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.077

T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.55

T;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.094

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

N;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.41

N;N

REVEL

Benign

0.099

Sift

Benign

0.41

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.053

B;.

Vest4

0.23

MutPred

0.39

Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);

MVP

0.49

MPC

0.19

ClinPred

0.18

GERP RS

2.6

Varity_R

0.068

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over