dbSNP rs5855: 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:

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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.

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	Effect	Exon Rank	Protein	UniProt
PAM	NM_001177306.2	MANE Select	c.*417G>A	3_prime_UTR	Exon 26 of 26	NP_001170777.1	P19021-1
PAM	NM_001319943.1		c.*417G>A	3_prime_UTR	Exon 27 of 27	NP_001306872.1	O43832
PAM	NM_000919.4		c.*417G>A	3_prime_UTR	Exon 26 of 26	NP_000910.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PAM	ENST00000438793.8	TSL:1 MANE Select	c.*417G>A	3_prime_UTR	Exon 26 of 26	ENSP00000396493.3	P19021-1
PAM	ENST00000304400.12	TSL:1	c.*417G>A	3_prime_UTR	Exon 26 of 26	ENSP00000306100.8	A0A8C8KD64
PAM	ENST00000348126.7	TSL:1	c.*417G>A	3_prime_UTR	Exon 25 of 25	ENSP00000314638.3	P19021-2

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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over