Genetic Variant PAM:p.Asp277Gly (chr5-102950745-A-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.830A>G(p.Asp277Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,610,860 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

PAM
NM_001177306.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.84

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.830A>G	p.Asp277Gly	missense_variant	Exon 12 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.830A>G	p.Asp277Gly	missense_variant	Exon 12 of 26	1	NM_001177306.2	ENSP00000396493.3		P19021-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250822

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135534

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1458856

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

725866

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000371

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.830A>G (p.D277G) alteration is located in exon 11 (coding exon 11) of the PAM gene. This alteration results from a A to G substitution at nucleotide position 830, causing the aspartic acid (D) at amino acid position 277 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;.;.;.;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Benign

0.069

MetaRNN

Uncertain

0.66

D;D;D;D;D

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.0

M;M;M;M;M

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.5

D;D;D;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.010

D;D;D;D;D

Sift4G

Uncertain

0.059

T;T;T;T;T

Polyphen

0.68

P;P;P;P;P

Vest4

0.60

MutPred

0.61

Gain of catalytic residue at V278 (P = 0.1395);Gain of catalytic residue at V278 (P = 0.1395);Gain of catalytic residue at V278 (P = 0.1395);Gain of catalytic residue at V278 (P = 0.1395);Gain of catalytic residue at V278 (P = 0.1395);

MVP

0.79

MPC

0.25

ClinPred

0.40

GERP RS

5.5

Varity_R

0.41

gMVP

0.76

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