Genetic Variant MCHR1:p.Asn13Lys (chr22-40679691-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005297.4(MCHR1):c.39C>A(p.Asn13Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MCHR1
NM_005297.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.05

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCHR1	NM_005297.4 link	c.39C>A	p.Asn13Lys	missense_variant	Exon 1 of 2	ENST00000249016.5	NP_005288.4	Q99705
LOC124905123	XR_007068109.1 link	n.4323+917G>T		intron_variant	Intron 1 of 1
LOC124905123	XR_007068110.1 link	n.358+917G>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCHR1	ENST00000249016.5 link	c.39C>A	p.Asn13Lys	missense_variant	Exon 1 of 2	1	NM_005297.4	ENSP00000249016.5		Q99705

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.22

CADD

Benign

3.0

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.75

T;T

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.55

N;.

PhyloP100

-1.0

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.18

Sift

Uncertain

0.020

D;D

Sift4G

Benign

0.066

T;T

Polyphen

1.0

D;.

Vest4

0.52

MutPred

0.42

Gain of ubiquitination at N82 (P = 0.0025);Gain of ubiquitination at N82 (P = 0.0025);

MVP

0.81

MPC

0.40

ClinPred

0.93

GERP RS

0.41

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.088

gMVP

0.68

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over