Variant 5-102867275-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001177306.2(PAM):c.92T>A(p.Phe31Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00187 in 1,599,074 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0087 ( 19 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 14 hom. )

Consequence

PAM
NM_001177306.2 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.54

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 made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042791665).

BP6

Variant 5-102867275-T-A is Benign according to our data. Variant chr5-102867275-T-A is described in ClinVar as [Benign]. Clinvar id is 780546.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00867 (1321/152308) while in subpopulation AFR AF= 0.0282 (1170/41556). AF 95% confidence interval is 0.0268. There are 19 homozygotes in gnomad4. There are 624 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAM	NM_001177306.2 linkuse as main transcript	c.92T>A	p.Phe31Tyr	missense_variant, splice_region_variant	3/26	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.92T>A	p.Phe31Tyr	missense_variant, splice_region_variant	3/26	1	NM_001177306.2	ENSP00000396493	P4	P19021-1

Frequencies

GnomAD3 genomes

AF:

0.00865

AC:

1317

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0281

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00726

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00242

AC:

606

AN:

250484

Hom.:

AF XY:

0.00182

AC XY:

247

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.0280

Gnomad AMR exome

AF:

0.00233

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000658

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000441

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.00115

AC:

1671

AN:

1446766

Hom.:

Cov.:

AF XY:

0.000998

AC XY:

719

AN XY:

720760

show subpopulations

Gnomad4 AFR exome

AF:

0.0296

Gnomad4 AMR exome

AF:

0.00289

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000583

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000343

Gnomad4 OTH exome

AF:

0.00276

GnomAD4 genome

AF:

0.00867

AC:

1321

AN:

152308

Hom.:

Cov.:

AF XY:

0.00838

AC XY:

624

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0282

Gnomad4 AMR

AF:

0.00725

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00162

Hom.:

Bravo

AF:

0.00986

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0281

AC:

124

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00281

AC:

341

Asia WGS

AF:

0.000867

AC:

AN:

3476

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

Aug 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.0050

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

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.044

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.79

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

MetaRNN

Benign

0.0043

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.26

.;.;.;N;N;N;N;N

MutationTaster

Benign

0.96

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

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.47

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

REVEL

Benign

0.069

Sift

Benign

0.62

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

Sift4G

Benign

0.84

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

Polyphen

0.0010, 0.0

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

Vest4

0.30, 0.32, 0.30, 0.29

MVP

0.51

MPC

0.25

ClinPred

0.0077

GERP RS

4.5

Varity_R

0.095

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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