chr2-25161594-G-T

Variant names:

• chr2-25161594-G-T
• NM_000939.4:c.291C>A
• POMC p.Ser97Arg

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000939.4(POMC):​c.291C>A​(p.Ser97Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POMC NM_000939.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.733
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11719766).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000939.4. 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
	POMC	NM_000939.4	MANE Select	c.291C>A	p.Ser97Arg	missense	Exon 3 of 3	NP_000930.1	P01189
	POMC	NM_001035256.3		c.291C>A	p.Ser97Arg	missense	Exon 4 of 4	NP_001030333.1	P01189
	POMC	NM_001319204.2		c.291C>A	p.Ser97Arg	missense	Exon 4 of 4	NP_001306133.1	P01189

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	ENST00000395826.7	TSL:2 MANE Select	c.291C>A	p.Ser97Arg	missense	Exon 3 of 3	ENSP00000379170.2	P01189
	POMC	ENST00000405623.5	TSL:1	c.291C>A	p.Ser97Arg	missense	Exon 3 of 3	ENSP00000384092.1	P01189
	POMC	ENST00000264708.7	TSL:2	c.291C>A	p.Ser97Arg	missense	Exon 4 of 4	ENSP00000264708.3	P01189

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1404164 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 693494

African (AFR) AF: 0.00 AC: 0 AN: 31806

American (AMR) AF: 0.00 AC: 0 AN: 36498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 36238

South Asian (SAS) AF: 0.00 AC: 0 AN: 80078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082124

Other (OTH) AF: 0.00 AC: 0 AN: 58182

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	4.5
DANN	Benign	0.85
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.73
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.20
Sift	Benign	0.031	D
Sift4G	Benign	0.49	T
Varity_R		0.054
gMVP		0.21
Mutation Taster		=97/3	polymorphism

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

hg19: chr2-25384463;