2-25161596-T-G

Variant names:

• chr2-25161596-T-G
• rs746125905
• NM_000939.4:c.289A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 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. 15/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.442

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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	c.289A>C	p.Ser97Arg	missense_variant	Exon 3 of 3	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.289A>C	p.Ser97Arg	missense_variant	Exon 4 of 4		NP_001030333.1
POMC	NM_001319204.2	c.289A>C	p.Ser97Arg	missense_variant	Exon 4 of 4		NP_001306133.1
POMC	NM_001319205.2	c.289A>C	p.Ser97Arg	missense_variant	Exon 3 of 3		NP_001306134.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000521 AC: 8 AN: 153482 Hom.: 0 AF XY: 0.0000120 AC XY: 1 AN XY: 83012

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 SAS 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: 14 AN: 1404498 Hom.: 0 Cov.: 33 AF XY: 0.00000865 AC XY: 6 AN XY: 693672

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000276

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000277

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000475 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	2.1
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	N
LIST_S2	Benign	0.57	T;.;.;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.029	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L;L;L;L;.
PrimateAI	Uncertain	0.78	T
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	T
GERP RS		-4.4
Varity_R		0.077
gMVP		0.21

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: rs746125905; hg19: chr2-25384465;