Variant rs35658696 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000438793.8(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
ENST00000438793.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.29

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 108 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAM	NM_001177306.2 linkuse as main transcript	c.1688A>G	p.Asp563Gly	missense_variant	17/26	ENST00000438793.8	NP_001170777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAM	ENST00000438793.8 linkuse as main transcript	c.1688A>G	p.Asp563Gly	missense_variant	17/26	1	NM_001177306.2	ENSP00000396493	P4	P19021-1

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

GnomAD3 exomes

AF:

0.0312

AC:

7821

AN:

250674

Hom.:

183

AF XY:

0.0317

AC XY:

4292

AN XY:

135474

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 SAS exome

AF:

0.0182

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

Gnomad4 AFR exome

AF:

0.00713

Gnomad4 AMR exome

AF:

0.0114

Gnomad4 ASJ exome

AF:

0.00365

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0186

Gnomad4 FIN exome

AF:

0.0594

Gnomad4 NFE exome

AF:

0.0500

Gnomad4 OTH exome

AF:

0.0367

GnomAD4 genome

AF:

0.0311

AC:

4731

AN:

152258

Hom.:

108

Cov.:

AF XY:

0.0306

AC XY:

2277

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00833

Gnomad4 AMR

AF:

0.0157

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0141

Gnomad4 FIN

AF:

0.0566

Gnomad4 NFE

AF:

0.0496

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.0411

Hom.:

251

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

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

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

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

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