Variant 11-10306612-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001124.3(ADM):c.529C>G(p.Pro177Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000672 in 1,562,692 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

ADM
NM_001124.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0640

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.006511897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADM	NM_001124.3 linkuse as main transcript	c.529C>G	p.Pro177Ala	missense_variant	4/4	ENST00000278175.10	NP_001115.1	P35318

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADM	ENST00000278175.10 linkuse as main transcript	c.529C>G	p.Pro177Ala	missense_variant	4/4	1	NM_001124.3	ENSP00000278175.5		P35318

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000151

AC:

AN:

205028

Hom.:

AF XY:

0.000115

AC XY:

AN XY:

112828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000372

Gnomad ASJ exome

AF:

0.000159

Gnomad EAS exome

AF:

0.0000629

Gnomad SAS exome

AF:

0.0000424

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.000212

GnomAD4 exome

AF:

0.0000546

AC:

AN:

1410370

Hom.:

Cov.:

AF XY:

0.0000602

AC XY:

AN XY:

697742

show subpopulations

Gnomad4 AFR exome

AF:

0.0000644

Gnomad4 AMR exome

AF:

0.000264

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000569

Gnomad4 OTH exome

AF:

0.0000518

GnomAD4 genome

AF:

0.000184

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000429

Hom.:

Bravo

AF:

0.000189

ExAC

AF:

0.000158

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.529C>G (p.P177A) alteration is located in exon 4 (coding exon 3) of the ADM gene. This alteration results from a C to G substitution at nucleotide position 529, causing the proline (P) at amino acid position 177 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

0.055

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.59

CADD

Benign

2.4

DANN

Benign

0.18

DEOGEN2

Benign

0.17

T;T;.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.42

.;T;T;.;T

M_CAP

Benign

0.0016

MetaRNN

Benign

0.0065

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;.;.;L;L

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.21

N;N;N;N;N

REVEL

Benign

0.022

Sift

Benign

0.39

T;T;T;T;T

Sift4G

Benign

0.092

T;T;T;T;T

Polyphen

0.0030

B;.;.;B;B

Vest4

0.12

MutPred

0.36

Loss of glycosylation at P177 (P = 0.012);.;.;Loss of glycosylation at P177 (P = 0.012);Loss of glycosylation at P177 (P = 0.012);

MVP

0.39

MPC

0.49

ClinPred

0.0047

GERP RS

0.16

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.050

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over