rs11914085

Positions:

• chr22-40680966-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005297.4(MCHR1):​c.100G>A​(p.Gly34Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00651 in 1,614,002 control chromosomes in the GnomAD database, including 603 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 0.034 (297 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (306 hom.)
• Consequence: MCHR1 NM_005297.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.0980

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018067956).
• BP6: Variant 22-40680966-G-A is Benign according to our data. Variant chr22-40680966-G-A is described in ClinVar as [Benign]. Clinvar id is 1284474.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-40680966-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCHR1	NM_005297.4	c.100G>A	p.Gly34Arg	missense_variant	2/2	ENST00000249016.5	NP_005288.4
LOC124905123	XR_007068110.1	n.189-189C>T		intron_variant, non_coding_transcript_variant
LOC124905123	XR_007068109.1	n.3965C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCHR1	ENST00000249016.5	c.100G>A	p.Gly34Arg	missense_variant	2/2	1	NM_005297.4	ENSP00000249016	P1
	ENST00000688408.2	n.198-189C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5149 AN: 152040 Hom.: 295 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.00882 AC: 2217 AN: 251270 Hom.: 111 AF XY: 0.00638 AC XY: 866 AN XY: 135842

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00365 AC: 5342 AN: 1461844 Hom.: 306 Cov.: 32 AF XY: 0.00315 AC XY: 2289 AN XY: 727230

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.00472

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000249

Gnomad4 OTH exome AF: 0.00767

GnomAD4 genome AF: 0.0339 AC: 5162 AN: 152158 Hom.: 297 Cov.: 32 AF XY: 0.0326 AC XY: 2423 AN XY: 74376

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.00733 Hom.: 88

Bravo AF: 0.0386

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.121 AC: 534

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0113 AC: 1368

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

MCHR1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.2
DANN	Benign	0.69
DEOGEN2	Benign	0.097	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.63	N;N
REVEL	Benign	0.017
Sift	Benign	0.59	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.0	B;.
Vest4		0.18
MutPred		0.11		Gain of glycosylation at P100 (P = 0.0791);Gain of glycosylation at P100 (P = 0.0791);
MPC		0.15
ClinPred		0.0028	T
GERP RS		1.6
Varity_R		0.044
gMVP		0.69

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: rs11914085; hg19: chr22-41076970;