Variant 5-102946885-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001177306.2(PAM):c.575C>T(p.Pro192Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,593,086 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0067 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 109 hom. )

Consequence

PAM
NM_001177306.2 missense, splice_region

Scores

Splicing: ADA: 0.8225

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.29

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:

PAM (HGNC:):

PAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009652853).

BP6

Variant 5-102946885-C-T is Benign according to our data. Variant chr5-102946885-C-T is described in ClinVar as [Benign]. Clinvar id is 777977.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.575C>T	p.Pro192Leu	missense_variant, splice_region_variant	8/26	ENST00000438793.8	NP_001170777.1	P19021-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAM	ENST00000438793.8 linkuse as main transcript	c.575C>T	p.Pro192Leu	missense_variant, splice_region_variant	8/26	1	NM_001177306.2	ENSP00000396493.3		P19021-1

Frequencies

GnomAD3 genomes

AF:

0.00671

AC:

1020

AN:

152012

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:

0.000578

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0125

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00680

AC:

1690

AN:

248434

Hom.:

AF XY:

0.00664

AC XY:

891

AN XY:

134206

show subpopulations

Gnomad AFR exome

AF:

0.00217

Gnomad AMR exome

AF:

0.00319

Gnomad ASJ exome

AF:

0.00460

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.000465

Gnomad FIN exome

AF:

0.00274

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.00762

GnomAD4 exome

AF:

0.0112

AC:

16161

AN:

1440956

Hom.:

109

Cov.:

AF XY:

0.0108

AC XY:

7731

AN XY:

717896

show subpopulations

Gnomad4 AFR exome

AF:

0.00160

Gnomad4 AMR exome

AF:

0.00312

Gnomad4 ASJ exome

AF:

0.00447

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.000445

Gnomad4 FIN exome

AF:

0.00336

Gnomad4 NFE exome

AF:

0.0138

Gnomad4 OTH exome

AF:

0.00824

GnomAD4 genome

AF:

0.00670

AC:

1020

AN:

152130

Hom.:

Cov.:

AF XY:

0.00613

AC XY:

456

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00210

Gnomad4 AMR

AF:

0.00249

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.0125

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:

0.00709

AC:

860

Asia WGS

AF:

0.00115

AC:

AN:

3478

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

0.17

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Uncertain

0.63

D;.;.;.;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.0097

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.8

L;L;L;L;L

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.6

D;D;D;D;D

REVEL

Benign

0.051

Sift

Uncertain

0.019

D;D;T;D;D

Sift4G

Uncertain

0.032

D;D;D;D;D

Polyphen

0.55

P;P;P;P;P

Vest4

0.39

MVP

0.59

MPC

0.66

ClinPred

0.040

GERP RS

4.5

Varity_R

0.15

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.82

dbscSNV1_RF

Benign

0.36

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