2-25161596-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000939.4(POMC):c.289A>C(p.Ser97Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000997 in 1,404,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

POMC
NM_000939.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -0.442

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

obesity due to pro-opiomelanocortin deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
inherited obesity
Inheritance: SD, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics

POMC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028620005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4 link	c.289A>C	p.Ser97Arg	missense_variant	Exon 3 of 3	ENST00000395826.7	NP_000930.1	P01189
POMC	NM_001035256.3 link	c.289A>C	p.Ser97Arg	missense_variant	Exon 4 of 4		NP_001030333.1	P01189
POMC	NM_001319204.2 link	c.289A>C	p.Ser97Arg	missense_variant	Exon 4 of 4		NP_001306133.1	P01189
POMC	NM_001319205.2 link	c.289A>C	p.Ser97Arg	missense_variant	Exon 3 of 3		NP_001306134.1	P01189

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7 link	c.289A>C	p.Ser97Arg	missense_variant	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2		P01189

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000521

AC:

AN:

153482

AF XY:

0.0000120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000317

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000997

AC:

AN:

1404498

Hom.:

Cov.:

AF XY:

0.00000865

AC XY:

AN XY:

693672

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31848

American (AMR)

AF:

0.000246

AC:

AN:

36520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25198

East Asian (EAS)

AF:

0.0000276

AC:

AN:

36230

South Asian (SAS)

AF:

0.00

AC:

AN:

80094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48400

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000277

AC:

AN:

1082308

Other (OTH)

AF:

0.00

AC:

AN:

58206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000475

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 01, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POMC-related disorder

Uncertain:1

Jan 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The POMC c.289A>C variant is predicted to result in the amino acid substitution p.Ser97Arg. To our knowledge, this variant has not been reported in the literature. This variant was evaluated in an in vitro functional studies with evidence of gain of function (Supplemental Data Set, Shah et al. 2023. PubMed ID: 36864747). Of note, other variants impacting the p.Ser97 amino acid were also evaluated; however, only one other variant showed evidence of gain of function (p.Ser97Ile) and other variants had functional data similar to wild type levels (p.Ser97Thr, p.Ser97Asn, p.Ser97Cys, and p.Ser97Gly). This variant is reported in 0.032% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.41

CADD

Benign

2.1

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.36

T;T;T;T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.57

T;.;.;.;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.029

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

L;L;L;L;.

PhyloP100

-0.44

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.84

N;N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.031

D;D;D;D;D

Sift4G

Benign

0.49

T;T;T;T;.

Polyphen

0.0040

B;B;B;B;.

Vest4

0.17

MutPred

0.30

Loss of phosphorylation at S97 (P = 0.006);Loss of phosphorylation at S97 (P = 0.006);Loss of phosphorylation at S97 (P = 0.006);Loss of phosphorylation at S97 (P = 0.006);Loss of phosphorylation at S97 (P = 0.006);

MVP

0.59

MPC

0.33

ClinPred

0.061

GERP RS

-4.4

Varity_R

0.077

gMVP

0.21

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over