Genetic Variant PAM:p.Val49Leu (chr5-102867328-G-C) – ACMG Classification: Benign (-10 pts)

Variant summary

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

The NM_001177306.2(PAM):c.145G>C(p.Val49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,600,974 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0093 ( 5 hom., cov: 32)

Exomes 𝑓: 0.013 ( 152 hom. )

Consequence

PAM
NM_001177306.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.10

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=0.004789859).

BP6

Variant 5-102867328-G-C is Benign according to our data. Variant chr5-102867328-G-C is described in ClinVar as [Benign]. Clinvar id is 773172.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAM	NM_001177306.2 link	c.145G>C	p.Val49Leu	missense_variant	Exon 3 of 26	ENST00000438793.8	NP_001170777.1	P19021-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAM	ENST00000438793.8 link	c.145G>C	p.Val49Leu	missense_variant	Exon 3 of 26	1	NM_001177306.2	ENSP00000396493.3		P19021-1

Frequencies

GnomAD3 genomes

AF:

0.00928

AC:

1411

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00372

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00708

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0136

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00856

AC:

2150

AN:

251190

Hom.:

AF XY:

0.00856

AC XY:

1162

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00302

Gnomad AMR exome

AF:

0.00429

Gnomad ASJ exome

AF:

0.00457

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000850

Gnomad FIN exome

AF:

0.0178

Gnomad NFE exome

AF:

0.0127

Gnomad OTH exome

AF:

0.00898

GnomAD4 exome

AF:

0.0128

AC:

18566

AN:

1448768

Hom.:

152

Cov.:

AF XY:

0.0126

AC XY:

9063

AN XY:

721646

show subpopulations

Gnomad4 AFR exome

AF:

0.00256

Gnomad4 AMR exome

AF:

0.00439

Gnomad4 ASJ exome

AF:

0.00469

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000977

Gnomad4 FIN exome

AF:

0.0173

Gnomad4 NFE exome

AF:

0.0150

Gnomad4 OTH exome

AF:

0.00983

GnomAD4 genome

AF:

0.00926

AC:

1410

AN:

152206

Hom.:

Cov.:

AF XY:

0.00919

AC XY:

684

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00371

Gnomad4 AMR

AF:

0.00707

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0180

Gnomad4 NFE

AF:

0.0135

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.0117

Hom.:

Bravo

AF:

0.00811

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0114

AC:

ExAC

AF:

0.00801

AC:

972

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0123

EpiControl

AF:

0.0139

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.089

T;.;T;.;.;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

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

MetaRNN

Benign

0.0048

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;.;L;L;L;L;L

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.1

N;N;N;N;N;N;N

REVEL

Benign

0.058

Sift

Benign

0.058

T;T;T;D;D;T;T

Sift4G

Benign

0.13

T;T;T;T;T;T;T

Polyphen

0.0, 0.0020

.;.;B;B;B;B;B

Vest4

0.33, 0.33, 0.33, 0.34, 0.34

MutPred

0.18

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.48

MPC

0.15

ClinPred

0.0095

GERP RS

3.9

Varity_R

0.044

gMVP

0.42

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