rs80326661

Positions:

chr2-25161244-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0052 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0070 ( 38 hom. )

Consequence

POMC
NM_000939.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.0140

Variant links:

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]

POMC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211936.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5}. 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. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMC	NM_000939.4 link	c.641A>G	p.Glu214Gly	missense_variant	3/3	ENST00000395826.7	NP_000930.1	P01189
POMC	NM_001035256.3 link	c.641A>G	p.Glu214Gly	missense_variant	4/4		NP_001030333.1	P01189
POMC	NM_001319204.2 link	c.641A>G	p.Glu214Gly	missense_variant	4/4		NP_001306133.1	P01189
POMC	NM_001319205.2 link	c.641A>G	p.Glu214Gly	missense_variant	3/3		NP_001306134.1	P01189

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7 link	c.641A>G	p.Glu214Gly	missense_variant	3/3	2	NM_000939.4	ENSP00000379170.2		P01189

Frequencies

GnomAD3 genomes

AF:

0.00524

AC:

793

AN:

151424

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00542

AC XY:

730

AN XY:

134752

show subpopulations

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.:

Cov.:

AF XY:

0.00683

AC XY:

4960

AN XY:

726312

show subpopulations

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.:

Cov.:

AF XY:

0.00478

AC XY:

354

AN XY:

74076

show subpopulations

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.:

Bravo

AF:

0.00411

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.00550

AC:

668

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00802

EpiControl

AF:

0.00634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	POMC: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2024	Identified in patients with obesity in published literature, although the variant did not segregate with disease in one family and was also found at a higher frequency in controls in another study (also reported as p.(Glu188Gly) using alternate nomenclature; PMID: 9768693, 12068494, 24890885, 29970488); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29970488, 9768693, 12068494, 24890885) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

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, no assertion criteria provided

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

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

LIST_S2

Benign

0.57

T;.;.;.;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.0090

T;T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.7

L;L;L;L;.

PrimateAI

Uncertain

0.56

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over