22-40679528-A-T

Position:

• chr22-40679528-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005297.4(MCHR1):​c.-125A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,613,458 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0096 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (105 hom.)
• Consequence: MCHR1 NM_005297.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.634

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=0.0039777756).
• BP6: Variant 22-40679528-A-T is Benign according to our data. Variant chr22-40679528-A-T is described in ClinVar as [Benign]. Clinvar id is 3059605.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-40679528-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00964 (1465/151946) while in subpopulation AFR AF= 0.0175 (725/41416). AF 95% confidence interval is 0.0164. There are 28 homozygotes in gnomad4. There are 760 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCHR1	NM_005297.4	c.-125A>T		5_prime_UTR_variant	1/2	ENST00000249016.5
LOC124905123	XR_007068110.1	n.358+1080T>A		intron_variant, non_coding_transcript_variant
LOC124905123	XR_007068109.1	n.4323+1080T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCHR1	ENST00000249016.5	c.-125A>T		5_prime_UTR_variant	1/2	1	NM_005297.4	P1
MCHR1	ENST00000381433.3	c.-125A>T		5_prime_UTR_variant	1/3	1
MCHR1	ENST00000498400.1	n.132+124A>T		intron_variant, non_coding_transcript_variant		1
	ENST00000688408.2	n.367+1080T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00958 AC: 1455 AN: 151828 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.00346

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00763 AC: 1904 AN: 249648 Hom.: 41 AF XY: 0.00745 AC XY: 1007 AN XY: 135198

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.00845

Gnomad ASJ exome AF: 0.0670

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00442

Gnomad OTH exome AF: 0.0167

GnomAD4 exome AF: 0.00477 AC: 6973 AN: 1461512 Hom.: 105 Cov.: 31 AF XY: 0.00494 AC XY: 3594 AN XY: 727046

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.00921

Gnomad4 ASJ exome AF: 0.0680

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00305

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.00258

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00964 AC: 1465 AN: 151946 Hom.: 28 Cov.: 33 AF XY: 0.0102 AC XY: 760 AN XY: 74296

Gnomad4 AFR AF: 0.0175

Gnomad4 AMR AF: 0.0143

Gnomad4 ASJ AF: 0.0646

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00344

Gnomad4 OTH AF: 0.0165

Alfa AF: 0.00960 Hom.: 24

Bravo AF: 0.0103

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00721 AC: 875

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.00747

EpiControl AF: 0.00729

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MCHR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

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	0.089
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.075	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.070	T;D
Polyphen		0.42	B;.
Vest4		0.40
MVP		0.79
MPC		0.19
ClinPred		0.012	T
GERP RS		-0.012
Varity_R		0.12
gMVP		0.30

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: rs112405400; hg19: chr22-41075532;