Genetic Variant PAM:c.2486-88A>C (chr5-103025043-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001177306.2(PAM):c.2486-88A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 843,236 control chromosomes in the GnomAD database, including 39,938 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 0.27 ( 6175 hom., cov: 31)

Exomes 𝑓: 0.31 ( 33763 hom. )

Consequence

PAM
NM_001177306.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0440

Publications

6 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAM	NM_001177306.2 link	c.2486-88A>C		intron_variant	Intron 23 of 25	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.2486-88A>C		intron_variant	Intron 23 of 25	1	NM_001177306.2	ENSP00000396493.3		P19021-1

Frequencies

GnomAD3 genomes

AF:

0.274

AC:

41635

AN:

151722

Hom.:

6177

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.438

Gnomad AMR

AF:

0.261

Gnomad ASJ

AF:

0.279

Gnomad EAS

AF:

0.365

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.333

Gnomad MID

AF:

0.213

Gnomad NFE

AF:

0.331

Gnomad OTH

AF:

0.283

GnomAD4 exome

AF:

0.305

AC:

210930

AN:

691396

Hom.:

33763

AF XY:

0.300

AC XY:

109186

AN XY:

364556

show subpopulations

African (AFR)

AF:

0.170

AC:

3050

AN:

17992

American (AMR)

AF:

0.228

AC:

7378

AN:

32388

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

4565

AN:

16898

East Asian (EAS)

AF:

0.377

AC:

13580

AN:

36014

South Asian (SAS)

AF:

0.162

AC:

9378

AN:

57894

European-Finnish (FIN)

AF:

0.334

AC:

12999

AN:

38956

Middle Eastern (MID)

AF:

0.198

AC:

579

AN:

2928

European-Non Finnish (NFE)

AF:

0.329

AC:

149161

AN:

453518

Other (OTH)

AF:

0.294

AC:

10240

AN:

34808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

7529

15058

22587

30116

37645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2576

5152

7728

10304

12880

<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:

0.274

AC:

41646

AN:

151840

Hom.:

6175

Cov.:

AF XY:

0.271

AC XY:

20104

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.169

AC:

6997

AN:

41452

American (AMR)

AF:

0.262

AC:

3986

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

968

AN:

3466

East Asian (EAS)

AF:

0.365

AC:

1882

AN:

5160

South Asian (SAS)

AF:

0.161

AC:

773

AN:

4804

European-Finnish (FIN)

AF:

0.333

AC:

3503

AN:

10512

Middle Eastern (MID)

AF:

0.199

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.331

AC:

22487

AN:

67906

Other (OTH)

AF:

0.282

AC:

594

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1460

2920

4381

5841

7301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

422

844

1266

1688

2110

<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:

0.173

Hom.:

383

Bravo

AF:

0.264

Asia WGS

AF:

0.248

AC:

864

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

9.6

(source)

DANN

Benign

0.69

PhyloP100

0.044

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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