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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P194S) has been classified as Uncertain significance.

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

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177306.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAM	NM_001177306.2	MANE Select	c.580C>G	p.Pro194Ala	missense	Exon 9 of 26	NP_001170777.1	P19021-1
PAM	NM_001319943.1		c.580C>G	p.Pro194Ala	missense	Exon 9 of 27	NP_001306872.1	O43832
PAM	NM_000919.4		c.580C>G	p.Pro194Ala	missense	Exon 9 of 26	NP_000910.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAM	ENST00000438793.8	TSL:1 MANE Select	c.580C>G	p.Pro194Ala	missense	Exon 9 of 26	ENSP00000396493.3	P19021-1
PAM	ENST00000304400.12	TSL:1	c.580C>G	p.Pro194Ala	missense	Exon 9 of 26	ENSP00000306100.8	A0A8C8KD64
PAM	ENST00000455264.7	TSL:1	c.580C>G	p.Pro194Ala	missense	Exon 9 of 25	ENSP00000403461.2	P19021-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000205

AC:

AN:

243924

AF XY:

0.0000228

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 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

African (AFR)

AF:

0.00

AC:

AN:

32280

American (AMR)

AF:

0.000162

AC:

AN:

43200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25654

East Asian (EAS)

AF:

0.00

AC:

AN:

39378

South Asian (SAS)

AF:

0.00

AC:

AN:

83084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4488

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075142

Other (OTH)

AF:

0.00

AC:

AN:

58726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

-0.096

MutationAssessor

Pathogenic

3.0

PhyloP100

6.2

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.51

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.044

Polyphen

1.0

Vest4

0.71

MutPred

0.65

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

Mutation Taster

=193/107

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over