Genetic Variant NM_001177306.2:c.-310C>G (chr5-102865886-C-G) – 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.-310C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 323,888 control chromosomes in the GnomAD database, including 39,423 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 0.51 ( 21910 hom., cov: 32)

Exomes 𝑓: 0.43 ( 17513 hom. )

Consequence

PAM
NM_001177306.2 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.17

Publications

20 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=-0.78).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAM	NM_001177306.2 link	c.-310C>G		5_prime_UTR_variant	Exon 2 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.-310C>G		5_prime_UTR_variant	Exon 2 of 26	1	NM_001177306.2	ENSP00000396493.3		P19021-1

Frequencies

GnomAD3 genomes

AF:

0.513

AC:

77983

AN:

151894

Hom.:

21840

Cov.:

show subpopulations

Gnomad AFR

AF:

0.722

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.544

Gnomad ASJ

AF:

0.457

Gnomad EAS

AF:

0.621

Gnomad SAS

AF:

0.664

Gnomad FIN

AF:

0.293

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.401

Gnomad OTH

AF:

0.506

GnomAD4 exome

AF:

0.435

AC:

74702

AN:

171878

Hom.:

17513

Cov.:

AF XY:

0.440

AC XY:

38536

AN XY:

87634

show subpopulations

African (AFR)

AF:

0.714

AC:

3025

AN:

4238

American (AMR)

AF:

0.583

AC:

2334

AN:

4002

Ashkenazi Jewish (ASJ)

AF:

0.452

AC:

2707

AN:

5994

East Asian (EAS)

AF:

0.607

AC:

6741

AN:

11102

South Asian (SAS)

AF:

0.655

AC:

5312

AN:

8104

European-Finnish (FIN)

AF:

0.301

AC:

4062

AN:

13480

Middle Eastern (MID)

AF:

0.479

AC:

438

AN:

914

European-Non Finnish (NFE)

AF:

0.399

AC:

44822

AN:

112432

Other (OTH)

AF:

0.453

AC:

5261

AN:

11612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1880

3760

5639

7519

9399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.514

AC:

78116

AN:

152010

Hom.:

21910

Cov.:

AF XY:

0.514

AC XY:

38190

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.723

AC:

29974

AN:

41472

American (AMR)

AF:

0.544

AC:

8323

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.457

AC:

1585

AN:

3470

East Asian (EAS)

AF:

0.622

AC:

3187

AN:

5124

South Asian (SAS)

AF:

0.663

AC:

3201

AN:

4826

European-Finnish (FIN)

AF:

0.293

AC:

3100

AN:

10584

Middle Eastern (MID)

AF:

0.551

AC:

162

AN:

294

European-Non Finnish (NFE)

AF:

0.401

AC:

27219

AN:

67928

Other (OTH)

AF:

0.509

AC:

1077

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1828

3655

5483

7310

9138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

678

1356

2034

2712

3390

<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:

0.452

Hom.:

2420

Bravo

AF:

0.541

Asia WGS

AF:

0.657

AC:

2287

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

2.2

PromoterAI

-0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=299/1

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