16-67483281-G-C

Variant names:

• chr16-67483281-G-C
• rs1055897200
• NM_001138.2:c.118C>G

Variant summary

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

The NM_001138.2(AGRP):​c.118C>G​(p.Pro40Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,587,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: AGRP NM_001138.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28
• Publications: 0 publications found

Genes affected

AGRP (HGNC:330): (agouti related neuropeptide) This gene encodes an antagonist of the melanocortin-3 and melanocortin-4 receptor. It appears to regulate hypothalamic control of feeding behavior via melanocortin receptor and/or intracellular calcium regulation, and thus plays a role in weight homeostasis. Mutations in this gene have been associated with late on-set obesity. [provided by RefSeq, Dec 2009]

ATP6V0D1-DT (HGNC:55268): (ATP6V0D1 divergent transcript)

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=0.13924274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRP	NM_001138.2	c.118C>G	p.Pro40Ala	missense_variant	Exon 2 of 4	ENST00000290953.3	NP_001129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRP	ENST00000290953.3	c.118C>G	p.Pro40Ala	missense_variant	Exon 2 of 4	1	NM_001138.2	ENSP00000290953.3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1435350 Hom.: 0 Cov.: 35 AF XY: 0.00000421 AC XY: 3 AN XY: 711940

African (AFR) AF: 0.0000917 AC: 3 AN: 32730

American (AMR) AF: 0.00 AC: 0 AN: 41242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24246

East Asian (EAS) AF: 0.00 AC: 0 AN: 39324

South Asian (SAS) AF: 0.00 AC: 0 AN: 82298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51742

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4926

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099792

Other (OTH) AF: 0.0000169 AC: 1 AN: 59050

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74360

African (AFR) AF: 0.000193 AC: 8 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.118C>G (p.P40A) alteration is located in exon 2 (coding exon 1) of the AGRP gene. This alteration results from a C to G substitution at nucleotide position 118, causing the proline (P) at amino acid position 40 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.060
Sift	Benign	0.13	T
Sift4G	Benign	0.59	T
Polyphen		0.27	B
Vest4		0.096
MutPred		0.63		Gain of loop (P = 0.0097);
MVP		0.27
MPC		0.74
ClinPred		0.38	T
GERP RS		1.5
PromoterAI		0.010	Neutral
Varity_R		0.086
gMVP		0.24
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1055897200; hg19: chr16-67517184;