dbSNP rs1216778690: PAM:p.Pro194Ala (chr5-102948382-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001177306.2(PAM):c.580C>G(p.Pro194Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000495 in 1,415,240 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

PAM
NM_001177306.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.22

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAM	NM_001177306.2 link	c.580C>G	p.Pro194Ala	missense_variant	Exon 9 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.580C>G	p.Pro194Ala	missense_variant	Exon 9 of 26	1	NM_001177306.2	ENSP00000396493.3		P19021-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000205

AC:

AN:

243924

Hom.:

AF XY:

0.0000228

AC XY:

AN XY:

131426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000152

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000495

AC:

AN:

1415240

Hom.:

Cov.:

AF XY:

0.00000425

AC XY:

AN XY:

706268

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000162

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Uncertain

0.71

D;.;.;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.73

D;D;D;D;D

MetaSVM

Uncertain

-0.096

MutationAssessor

Pathogenic

3.0

M;M;M;M;M

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.5

D;D;D;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0090

D;D;T;D;D

Sift4G

Uncertain

0.044

D;D;T;D;T

Polyphen

1.0

D;D;D;D;D

Vest4

0.71

MutPred

0.65

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.83

MPC

0.16

ClinPred

0.70

GERP RS

5.8

Varity_R

0.27

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: 0

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