dbSNP rs781336657: ADM:p.Pro174Ala (chr11-10306603-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001124.3(ADM):c.520C>G(p.Pro174Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000492 in 1,423,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P174S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

ADM
NM_001124.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0560

Variant links:

Genes affected

ADM (HGNC:259): (adrenomedullin) The protein encoded by this gene is a preprohormone which is cleaved to form two biologically active peptides, adrenomedullin and proadrenomedullin N-terminal 20 peptide. Adrenomedullin is a 52 aa peptide with several functions, including vasodilation, regulation of hormone secretion, promotion of angiogenesis, and antimicrobial activity. The antimicrobial activity is antibacterial, as the peptide has been shown to kill E. coli and S. aureus at low concentration. [provided by RefSeq, Aug 2014]

ADM links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08596721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADM	NM_001124.3 link	c.520C>G	p.Pro174Ala	missense_variant	Exon 4 of 4	ENST00000278175.10	NP_001115.1	P35318

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADM	ENST00000278175.10 link	c.520C>G	p.Pro174Ala	missense_variant	Exon 4 of 4	1	NM_001124.3	ENSP00000278175.5		P35318

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000138

AC:

AN:

217354

Hom.:

AF XY:

0.0000251

AC XY:

AN XY:

119746

show subpopulations

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:

0.000115

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000492

AC:

AN:

1423124

Hom.:

Cov.:

AF XY:

0.00000993

AC XY:

AN XY:

705240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000731

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000166

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.47

CADD

Benign

8.3

DANN

Benign

0.93

DEOGEN2

Benign

0.22

T;T;.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.51

.;T;T;.;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.086

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.;L;L

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.0

N;N;N;N;N

REVEL

Benign

0.018

Sift

Benign

0.040

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.0060

B;.;.;B;B

Vest4

0.21

MutPred

0.34

Loss of glycosylation at P174 (P = 0.0243);.;.;Loss of glycosylation at P174 (P = 0.0243);Loss of glycosylation at P174 (P = 0.0243);

MVP

0.48

MPC

0.49

ClinPred

0.025

GERP RS

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.052

gMVP

0.34

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over