16-67483385-G-A

Variant names:

• chr16-67483385-G-A
• rs745643706
• NM_001138.2:c.14C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001138.2(AGRP):​c.14C>T​(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,516,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: AGRP NM_001138.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.72
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04149291).
• BP6: Variant 16-67483385-G-A is Benign according to our data. Variant chr16-67483385-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3097174.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRP	NM_001138.2	c.14C>T	p.Ala5Val	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.14C>T	p.Ala5Val	missense_variant	Exon 2 of 4	1	NM_001138.2	ENSP00000290953.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.0000397 AC: 7 AN: 176226 AF XY: 0.0000320

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000183 AC: 25 AN: 1364252 Hom.: 0 Cov.: 34 AF XY: 0.0000180 AC XY: 12 AN XY: 668142

African (AFR) AF: 0.0000659 AC: 2 AN: 30328

American (AMR) AF: 0.00 AC: 0 AN: 29890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20026

East Asian (EAS) AF: 0.00 AC: 0 AN: 38714

South Asian (SAS) AF: 0.0000425 AC: 3 AN: 70556

European-Finnish (FIN) AF: 0.0000411 AC: 2 AN: 48668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5218

European-Non Finnish (NFE) AF: 0.0000169 AC: 18 AN: 1064744

Other (OTH) AF: 0.00 AC: 0 AN: 56108

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000251 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 19, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.0
DANN	Benign	0.62
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	N
PhyloP100		1.7
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.036
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.044
MutPred		0.51		Loss of helix (P = 0.0376);
MVP		0.20
MPC		0.34
ClinPred		0.016	T
GERP RS		2.9
PromoterAI		0.0083	Neutral
Varity_R		0.026
gMVP		0.33
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs745643706; hg19: chr16-67517288;