rs17296280

Positions:

• chr5-103025043-A-C
• chr5-103025043-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0440

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
PAM	NM_001177306.2	c.2486-88A>C		intron_variant		ENST00000438793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAM	ENST00000438793.8	c.2486-88A>C		intron_variant		1	NM_001177306.2	P4

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41635 AN: 151722 Hom.: 6177 Cov.: 31

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

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.377

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.334

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.294

GnomAD4 genome AF: 0.274 AC: 41646 AN: 151840 Hom.: 6175 Cov.: 31 AF XY: 0.271 AC XY: 20104 AN XY: 74196

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.262

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.333

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.282

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
DANN	Benign	0.69

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

Other links and lift over

dbSNP: rs17296280; hg19: chr5-102360747; COSMIC: COSV57211114;