rs34650613

Variant names:

• chr2-25161539-G-A
• rs34650613
• NM_000939.4:c.346C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000939.4(POMC):​c.346C>T​(p.Leu116Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,579,544 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (10 hom.)
• Consequence: POMC NM_000939.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.925
• Publications: 1 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):

• inherited obesity

  Inheritance: AD, SD Classification: STRONG, LIMITED Submitted by: Ambry Genetics
• obesity due to pro-opiomelanocortin deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-25161539-G-A is Benign according to our data. Variant chr2-25161539-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 728820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.925 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00247 (376/151942) while in subpopulation NFE AF = 0.00398 (271/68020). AF 95% confidence interval is 0.00359. There are 3 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,SD,AD gene

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.346C>T	p.Leu116Leu	synonymous	Exon 3 of 3	NP_000930.1	P01189
	POMC	NM_001035256.3		c.346C>T	p.Leu116Leu	synonymous	Exon 4 of 4	NP_001030333.1	P01189
	POMC	NM_001319204.2		c.346C>T	p.Leu116Leu	synonymous	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.346C>T	p.Leu116Leu	synonymous	Exon 3 of 3	ENSP00000379170.2	P01189
	POMC	ENST00000405623.5	TSL:1	c.346C>T	p.Leu116Leu	synonymous	Exon 3 of 3	ENSP00000384092.1	P01189
	POMC	ENST00000264708.7	TSL:2	c.346C>T	p.Leu116Leu	synonymous	Exon 4 of 4	ENSP00000264708.3	P01189

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 376 AN: 151824 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000681

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00259 AC: 474 AN: 183266 AF XY: 0.00259

Gnomad AFR exome AF: 0.000632

Gnomad AMR exome AF: 0.000139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00738

Gnomad NFE exome AF: 0.00446

Gnomad OTH exome AF: 0.00144

GnomAD4 exome AF: 0.00396 AC: 5649 AN: 1427602 Hom.: 10 Cov.: 32 AF XY: 0.00383 AC XY: 2708 AN XY: 706970

African (AFR) AF: 0.000429 AC: 14 AN: 32666

American (AMR) AF: 0.000223 AC: 9 AN: 40340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25462

East Asian (EAS) AF: 0.00 AC: 0 AN: 37988

South Asian (SAS) AF: 0.00 AC: 0 AN: 82568

European-Finnish (FIN) AF: 0.00508 AC: 248 AN: 48856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00478 AC: 5237 AN: 1095112

Other (OTH) AF: 0.00239 AC: 141 AN: 58904

GnomAD4 genome AF: 0.00247 AC: 376 AN: 151942 Hom.: 3 Cov.: 33 AF XY: 0.00273 AC XY: 203 AN XY: 74300

African (AFR) AF: 0.000679 AC: 28 AN: 41236

American (AMR) AF: 0.000458 AC: 7 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00631 AC: 67 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00398 AC: 271 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00329 Hom.: 2

Bravo AF: 0.00205

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Obesity (1)
-	-	1	POMC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.74
PhyloP100		0.93
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs34650613; hg19: chr2-25384408;