rs34114122

Variant names:

• chr18-60372527-T-G
• rs34114122
• NM_005912.3:c.-178A>C

Your query was ambiguous. Multiple possible variants found:

• chr18-60372527-T-G
• chr18-60372527-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005912.3(MC4R):​c.-178A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 676,096 control chromosomes in the GnomAD database, including 565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (318 hom., cov: 32)
  • Exomes 𝑓: 0.021 (247 hom.)
• Consequence: MC4R NM_005912.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.138
• Publications: 15 publications found

Genes affected

MC4R (HGNC:6932): (melanocortin 4 receptor) The protein encoded by this gene is a membrane-bound receptor and member of the melanocortin receptor family. The encoded protein interacts with adrenocorticotropic and MSH hormones and is mediated by G proteins. This is an intronless gene. Defects in this gene are a cause of autosomal dominant obesity. [provided by RefSeq, Jan 2010]

MC4R Gene-Disease associations (from GenCC):

• inherited obesity

  Inheritance: AD Classification: STRONG Submitted by: Laboratory for Molecular Medicine
• obesity due to melanocortin 4 receptor deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285681 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 18-60372527-T-G is Benign according to our data. Variant chr18-60372527-T-G is described in ClinVar as Benign. ClinVar VariationId is 327719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005912.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	NM_005912.3	MANE Select	c.-178A>C		5_prime_UTR	Exon 1 of 1	NP_005903.2	P32245

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	ENST00000299766.5	TSL:6 MANE Select	c.-178A>C		5_prime_UTR	Exon 1 of 1	ENSP00000299766.3	P32245
	ENSG00000285681	ENST00000650201.1		n.113+43182T>G		intron	N/A
	ENSG00000285681	ENST00000658928.1		n.156+43182T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0436 AC: 6640 AN: 152222 Hom.: 316 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0323

Gnomad SAS AF: 0.0395

Gnomad FIN AF: 0.00357

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0344

GnomAD4 exome AF: 0.0207 AC: 10816 AN: 523756 Hom.: 247 Cov.: 5 AF XY: 0.0207 AC XY: 5781 AN XY: 279692

African (AFR) AF: 0.121 AC: 1723 AN: 14184

American (AMR) AF: 0.0162 AC: 446 AN: 27538

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 75 AN: 16340

East Asian (EAS) AF: 0.0460 AC: 1452 AN: 31534

South Asian (SAS) AF: 0.0377 AC: 2005 AN: 53194

European-Finnish (FIN) AF: 0.00449 AC: 204 AN: 45396

Middle Eastern (MID) AF: 0.0139 AC: 30 AN: 2158

European-Non Finnish (NFE) AF: 0.0139 AC: 4227 AN: 304928

Other (OTH) AF: 0.0230 AC: 654 AN: 28484

GnomAD4 genome AF: 0.0436 AC: 6646 AN: 152340 Hom.: 318 Cov.: 32 AF XY: 0.0422 AC XY: 3145 AN XY: 74502

African (AFR) AF: 0.119 AC: 4942 AN: 41568

American (AMR) AF: 0.0206 AC: 315 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.0322 AC: 167 AN: 5188

South Asian (SAS) AF: 0.0389 AC: 188 AN: 4832

European-Finnish (FIN) AF: 0.00357 AC: 38 AN: 10630

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0133 AC: 907 AN: 68026

Other (OTH) AF: 0.0345 AC: 73 AN: 2116

Alfa AF: 0.0246 Hom.: 400

Bravo AF: 0.0475

Asia WGS AF: 0.0440 AC: 151 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Obesity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.76
PhyloP100		-0.14
PromoterAI		-0.0040	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34114122;

hg19: chr18-58039760;