dbSNP rs35658696: PAM:p.Asp563Gly (chr5-103003107-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001177306.2(PAM):c.1688A>G(p.Asp563Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,599,210 control chromosomes in the GnomAD database, including 1,705 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.031 ( 108 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1597 hom. )

Consequence

PAM
NM_001177306.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.29

Publications

47 publications found

Variant links:

Genes affected

PAM (HGNC:8596): (peptidylglycine alpha-amidating monooxygenase) This gene encodes a multifunctional protein. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme includes two domains with distinct catalytic activities, a peptidylglycine alpha-hydroxylating monooxygenase (PHM) domain and a peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) domain. These catalytic domains work sequentially to catalyze the conversion of neuroendocrine peptides to active alpha-amidated products. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

PAM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008397847).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0311 (4731/152258) while in subpopulation NFE AF = 0.0496 (3370/67996). AF 95% confidence interval is 0.0482. There are 108 homozygotes in GnomAd4. There are 2277 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 108 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAM	NM_001177306.2 link	c.1688A>G	p.Asp563Gly	missense_variant	Exon 17 of 26	ENST00000438793.8	NP_001170777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAM	ENST00000438793.8 link	c.1688A>G	p.Asp563Gly	missense_variant	Exon 17 of 26	1	NM_001177306.2	ENSP00000396493.3

Frequencies

GnomAD3 genomes

AF:

0.0311

AC:

4730

AN:

152140

Hom.:

108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00835

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0157

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.0566

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0495

Gnomad OTH

AF:

0.0267

GnomAD2 exomes

AF:

0.0312

AC:

7821

AN:

250674

AF XY:

0.0317

show subpopulations

Gnomad AFR exome

AF:

0.00844

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0609

Gnomad NFE exome

AF:

0.0459

Gnomad OTH exome

AF:

0.0324

GnomAD4 exome

AF:

0.0434

AC:

62784

AN:

1446952

Hom.:

1597

Cov.:

AF XY:

0.0424

AC XY:

30587

AN XY:

720872

show subpopulations

African (AFR)

AF:

0.00713

AC:

237

AN:

33220

American (AMR)

AF:

0.0114

AC:

507

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.00365

AC:

AN:

26028

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39588

South Asian (SAS)

AF:

0.0186

AC:

1599

AN:

85948

European-Finnish (FIN)

AF:

0.0594

AC:

3169

AN:

53364

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0500

AC:

54891

AN:

1098518

Other (OTH)

AF:

0.0367

AC:

2201

AN:

59900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

2426

4853

7279

9706

12132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2008

4016

6024

8032

10040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0311

AC:

4731

AN:

152258

Hom.:

108

Cov.:

AF XY:

0.0306

AC XY:

2277

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00833

AC:

346

AN:

41560

American (AMR)

AF:

0.0157

AC:

240

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0141

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0566

AC:

600

AN:

10606

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0496

AC:

3370

AN:

67996

Other (OTH)

AF:

0.0260

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

236

472

709

945

1181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0405

Hom.:

488

Bravo

AF:

0.0268

TwinsUK

AF:

0.0545

AC:

202

ALSPAC

AF:

0.0579

AC:

223

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.0493

AC:

424

ExAC

AF:

0.0322

AC:

3908

Asia WGS

AF:

0.00404

AC:

AN:

3476

EpiCase

AF:

0.0387

EpiControl

AF:

0.0416

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;.;.;.

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D

MetaRNN

Benign

0.0084

T;T;T;T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.1

M;M;.;M;M

PhyloP100

8.3

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-4.4

D;D;D;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0040

D;D;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D;D

Polyphen

0.99

D;D;D;D;D

Vest4

0.35

MPC

0.75

ClinPred

0.016

GERP RS

5.9

Varity_R

0.47

gMVP

0.82

Mutation Taster

=279/21

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over