rs80326661

chr2-25161244-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000939.4(POMC):c.641A>G(p.Glu214Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,611,820 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E214E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0052 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0070 (38 hom.)
• Consequence: POMC NM_000939.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0140

Genes affected

POMC (HGNC:9201): (proopiomelanocortin) This gene encodes a preproprotein that undergoes extensive, tissue-specific, post-translational processing via cleavage by subtilisin-like enzymes known as prohormone convertases. There are eight potential cleavage sites within the preproprotein and, depending on tissue type and the available convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions. The encoded protein is synthesized mainly in corticotroph cells of the anterior pituitary where four cleavage sites are used; adrenocorticotrophin, essential for normal steroidogenesis and the maintenance of normal adrenal weight, and lipotropin beta are the major end products. In other tissues, including the hypothalamus, placenta, and epithelium, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis, melanocyte stimulation, and immune modulation. These include several distinct melanotropins, lipotropins, and endorphins that are contained within the adrenocorticotrophin and beta-lipotropin peptides. The antimicrobial melanotropin alpha peptide exhibits antibacterial and antifungal activity. Mutations in this gene have been associated with early onset obesity, adrenal insufficiency, and red hair pigmentation. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008984923).
• BP6: Variant 2-25161244-T-C is Benign according to our data. Variant chr2-25161244-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 211936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-25161244-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00523 (793/151544) while in subpopulation NFE AF= 0.00919 (623/67802). AF 95% confidence interval is 0.00859. There are 7 homozygotes in gnomad4. There are 354 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMC	NM_000939.4	c.641A>G	p.Glu214Gly	missense_variant	3/3	ENST00000395826.7
POMC	NM_001035256.3	c.641A>G	p.Glu214Gly	missense_variant	4/4
POMC	NM_001319204.2	c.641A>G	p.Glu214Gly	missense_variant	4/4
POMC	NM_001319205.2	c.641A>G	p.Glu214Gly	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMC	ENST00000395826.7	c.641A>G	p.Glu214Gly	missense_variant	3/3	2	NM_000939.4	P1

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 793 AN: 151424 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00405

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000836

Gnomad FIN AF: 0.00825

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00919

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00542 AC: 1348 AN: 248690 Hom.: 5 AF XY: 0.00542 AC XY: 730 AN XY: 134752

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00429

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00138

Gnomad FIN exome AF: 0.00898

Gnomad NFE exome AF: 0.00883

Gnomad OTH exome AF: 0.00478

GnomAD4 exome AF: 0.00695 AC: 10154 AN: 1460276 Hom.: 38 Cov.: 32 AF XY: 0.00683 AC XY: 4960 AN XY: 726312

Gnomad4 AFR exome AF: 0.000867

Gnomad4 AMR exome AF: 0.000918

Gnomad4 ASJ exome AF: 0.00464

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.00813

Gnomad4 OTH exome AF: 0.00434

GnomAD4 genome AF: 0.00523 AC: 793 AN: 151544 Hom.: 7 Cov.: 33 AF XY: 0.00478 AC XY: 354 AN XY: 74076

Gnomad4 AFR AF: 0.00107

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.00405

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000837

Gnomad4 FIN AF: 0.00825

Gnomad4 NFE AF: 0.00919

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00760 Hom.: 3

Bravo AF: 0.00411

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00550 AC: 668

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00802

EpiControl AF: 0.00634

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	POMC: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 25, 2019

- -

POMC-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

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

Obesity Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	7.2
Dann	Benign	0.96
DEOGEN2	Uncertain	0.69	D;D;D;D;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.57	T;.;.;.;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.0090	T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.7	L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.033	D;D;D;D;D
Sift4G	Benign	0.21	T;T;T;T;.
Polyphen		0.54	P;P;P;P;.
Vest4		0.078
MVP		0.82
MPC		0.35
ClinPred		0.020	T
GERP RS		-2.6
Varity_R		0.060
gMVP		0.19

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: rs80326661; hg19: chr2-25384113; COSMIC: COSV104585116; COSMIC: COSV104585116;