Variant 5-102974426-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000438793.8(PAM):c.1473A>C(p.Glu491Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,611,724 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0067 ( 8 hom., cov: 32)

Exomes 𝑓: 0.012 ( 115 hom. )

Consequence

PAM
ENST00000438793.8 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.357

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047815144).

BP6

Variant 5-102974426-A-C is Benign according to our data. Variant chr5-102974426-A-C is described in ClinVar as [Benign]. Clinvar id is 777979.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAM	NM_001177306.2 linkuse as main transcript	c.1473A>C	p.Glu491Asp	missense_variant	15/26	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.1473A>C	p.Glu491Asp	missense_variant	15/26	1	NM_001177306.2	ENSP00000396493	P4	P19021-1

Frequencies

GnomAD3 genomes

AF:

0.00666

AC:

1014

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0124

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00701

AC:

1744

AN:

248758

Hom.:

AF XY:

0.00689

AC XY:

926

AN XY:

134468

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00317

Gnomad ASJ exome

AF:

0.00466

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000494

Gnomad FIN exome

AF:

0.00285

Gnomad NFE exome

AF:

0.0128

Gnomad OTH exome

AF:

0.00760

GnomAD4 exome

AF:

0.0116

AC:

16946

AN:

1459404

Hom.:

115

Cov.:

AF XY:

0.0112

AC XY:

8111

AN XY:

725996

show subpopulations

Gnomad4 AFR exome

AF:

0.00159

Gnomad4 AMR exome

AF:

0.00309

Gnomad4 ASJ exome

AF:

0.00450

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.00343

Gnomad4 NFE exome

AF:

0.0143

Gnomad4 OTH exome

AF:

0.00874

GnomAD4 genome

AF:

0.00666

AC:

1014

AN:

152320

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

452

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.00248

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.0124

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.00681

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0142

AC:

122

ExAC

AF:

0.00741

AC:

899

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.0122

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.21

T;.;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.80

T;T;T;T

MetaRNN

Benign

0.0048

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L;L;L

MutationTaster

Benign

1.0

D;D;N;N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.70

N;N;N;N

REVEL

Benign

0.040

Sift

Benign

0.39

T;T;T;T

Sift4G

Benign

0.60

T;T;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.18

MutPred

0.25

Loss of catalytic residue at E491 (P = 0.0762);Loss of catalytic residue at E491 (P = 0.0762);Loss of catalytic residue at E491 (P = 0.0762);Loss of catalytic residue at E491 (P = 0.0762);

MVP

0.56

MPC

0.14

ClinPred

0.0051

GERP RS

-1.4

Varity_R

0.084

gMVP

0.37

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