Genetic Variant ADM5:p.Arg90Leu (chr19-49690300-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001101340.2(ADM5):c.269G>T(p.Arg90Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 1,551,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

ADM5
NM_001101340.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.05

Publications

0 publications found

Variant links:

Genes affected

ADM5 (HGNC:27293): (adrenomedullin 5 (putative)) Predicted to be involved in several processes, including adenylate cyclase-activating G protein-coupled receptor signaling pathway; positive regulation of heart rate; and regulation of urine volume. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ADM5 links:

ENSG00000268677 (HGNC:):

ENSG00000268677 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040421188).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101340.2. 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
	ADM5	NM_001101340.2	MANE Select	c.269G>T	p.Arg90Leu	missense	Exon 2 of 2	NP_001094810.1	C9JUS6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADM5	ENST00000420022.4	TSL:1 MANE Select	c.269G>T	p.Arg90Leu	missense	Exon 2 of 2	ENSP00000393631.2	C9JUS6
ADM5	ENST00000968029.1		c.269G>T	p.Arg90Leu	missense	Exon 3 of 3	ENSP00000638088.1
ENSG00000268677	ENST00000596472.1	TSL:2	n.256+18C>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000654

AC:

AN:

152958

AF XY:

0.0000123

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000170

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1399018

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

690002

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31592

American (AMR)

AF:

0.00

AC:

AN:

35682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25158

East Asian (EAS)

AF:

0.00

AC:

AN:

35730

South Asian (SAS)

AF:

0.00

AC:

AN:

79194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000278

AC:

AN:

1078766

Other (OTH)

AF:

0.0000172

AC:

AN:

57988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.096

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.089

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.28

M_CAP

Benign

0.0011

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-4.1

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.059

Sift

Benign

0.15

Polyphen

0.0

Vest4

0.11

MutPred

0.15

Loss of methylation at R90 (P = 0.0095)

MVP

0.014

MPC

0.50

ClinPred

0.041

GERP RS

-4.5

Varity_R

0.055

gMVP

0.051

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over