2-25161280-T-TGGGCCC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM4 BS1_Supporting

The NM_000939.4(POMC):c.604_605insGGGCCC(p.Ala201_Gln202insArgAla) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,611,452 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: POMC NM_000939.4 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.894

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000939.4.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000381 (58/152114) while in subpopulation NFE AF= 0.000647 (44/67980). AF 95% confidence interval is 0.000495. There are 1 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMC	NM_000939.4	c.604_605insGGGCCC	p.Ala201_Gln202insArgAla	inframe_insertion	3/3	ENST00000395826.7
POMC	NM_001035256.3	c.604_605insGGGCCC	p.Ala201_Gln202insArgAla	inframe_insertion	4/4
POMC	NM_001319204.2	c.604_605insGGGCCC	p.Ala201_Gln202insArgAla	inframe_insertion	4/4
POMC	NM_001319205.2	c.604_605insGGGCCC	p.Ala201_Gln202insArgAla	inframe_insertion	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMC	ENST00000395826.7	c.604_605insGGGCCC	p.Ala201_Gln202insArgAla	inframe_insertion	3/3	2	NM_000939.4	P1

Frequencies

GnomAD3 genomes AF: 0.000382 AC: 58 AN: 151998 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000393 AC: 95 AN: 241952 Hom.: 0 AF XY: 0.000334 AC XY: 44 AN XY: 131716

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00150

Gnomad NFE exome AF: 0.000560

Gnomad OTH exome AF: 0.000507

GnomAD4 exome AF: 0.000345 AC: 503 AN: 1459338 Hom.: 0 Cov.: 32 AF XY: 0.000347 AC XY: 252 AN XY: 725826

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.000370

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152114 Hom.: 1 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000987 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2016	The c.599_604dupGGGCCC variant in the POMC gene has been reported previously, according to alternate nomeclature, in cis with a nonsense variant (E206X) and in trans with a missense variant (E214G), in a German adolescent female with obesity (Hinney et al., 1998). The c.599_604dupGGGCCC variant results in an in-frame insertion of two residues, an Arginine and an Alanine, at position 202 in the protein, denoted p.Ala201_Gln202insArgAla. The c.599_604dupGGGCCC variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, we interpret c.599_604dupGGGCCC as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This variant, c.599_604dup, results in the insertion of 2 amino acid(s) of the POMC protein (p.Ala201_Gln202insArgAla), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762710034, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with obesity, in cis with a nearby nonsense variant (PMID: 9768693, 29970488, 35574020). ClinVar contains an entry for this variant (Variation ID: 420163). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Obesity;C1260926:Abnormality of skin pigmentation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

May 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs762710034; hg19: chr2-25384149;