Genetic Variant PAM:c.*417G>A (chr5-103029482-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_001177306.2(PAM):c.*417G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.689 in 155,140 control chromosomes in the GnomAD database, including 37,036 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.69 ( 36265 hom., cov: 32)

Exomes 𝑓: 0.70 ( 771 hom. )

Consequence

PAM
NM_001177306.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.43

Publications

17 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.19).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAM	NM_001177306.2 link	c.*417G>A		3_prime_UTR_variant	Exon 26 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.*417G>A		3_prime_UTR_variant	Exon 26 of 26	1	NM_001177306.2	ENSP00000396493.3		P19021-1

Frequencies

GnomAD3 genomes

AF:

0.689

AC:

104708

AN:

151962

Hom.:

36249

Cov.:

show subpopulations

Gnomad AFR

AF:

0.681

Gnomad AMI

AF:

0.571

Gnomad AMR

AF:

0.741

Gnomad ASJ

AF:

0.752

Gnomad EAS

AF:

0.549

Gnomad SAS

AF:

0.847

Gnomad FIN

AF:

0.679

Gnomad MID

AF:

0.771

Gnomad NFE

AF:

0.680

Gnomad OTH

AF:

0.707

GnomAD4 exome

AF:

0.704

AC:

2155

AN:

3060

Hom.:

771

Cov.:

AF XY:

0.700

AC XY:

1141

AN XY:

1630

show subpopulations

African (AFR)

AF:

0.767

AC:

AN:

116

American (AMR)

AF:

0.758

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.674

AC:

AN:

138

East Asian (EAS)

AF:

0.579

AC:

AN:

South Asian (SAS)

AF:

0.813

AC:

AN:

European-Finnish (FIN)

AF:

0.687

AC:

356

AN:

518

Middle Eastern (MID)

AF:

0.917

AC:

AN:

European-Non Finnish (NFE)

AF:

0.709

AC:

1372

AN:

1936

Other (OTH)

AF:

0.688

AC:

117

AN:

170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.689

AC:

104780

AN:

152080

Hom.:

36265

Cov.:

AF XY:

0.692

AC XY:

51417

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.681

AC:

28240

AN:

41466

American (AMR)

AF:

0.741

AC:

11326

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.752

AC:

2610

AN:

3472

East Asian (EAS)

AF:

0.549

AC:

2830

AN:

5158

South Asian (SAS)

AF:

0.847

AC:

4084

AN:

4824

European-Finnish (FIN)

AF:

0.679

AC:

7182

AN:

10578

Middle Eastern (MID)

AF:

0.788

AC:

230

AN:

292

European-Non Finnish (NFE)

AF:

0.680

AC:

46260

AN:

67982

Other (OTH)

AF:

0.709

AC:

1497

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1664

3328

4991

6655

8319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.691

Hom.:

51881

Bravo

AF:

0.691

Asia WGS

AF:

0.722

AC:

2513

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over