rs28092

Positions:

• chr5-102814091-G-A
• chr5-102814091-G-T

Variant summary

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

The ENST00000438793.8(PAM):​c.-373-51732G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 152,088 control chromosomes in the GnomAD database, including 37,718 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 0.70 (37718 hom., cov: 31)
• Consequence: PAM ENST00000438793.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.901

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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAM	NM_001177306.2	c.-373-51732G>A		intron_variant		ENST00000438793.8	NP_001170777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAM	ENST00000438793.8	c.-373-51732G>A		intron_variant		1	NM_001177306.2	ENSP00000396493	P4

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106413 AN: 151970 Hom.: 37663 Cov.: 31

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.793

Gnomad EAS AF: 0.736

Gnomad SAS AF: 0.800

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.730

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.700 AC: 106528 AN: 152088 Hom.: 37718 Cov.: 31 AF XY: 0.704 AC XY: 52309 AN XY: 74336

Gnomad4 AFR AF: 0.780

Gnomad4 AMR AF: 0.726

Gnomad4 ASJ AF: 0.793

Gnomad4 EAS AF: 0.736

Gnomad4 SAS AF: 0.801

Gnomad4 FIN AF: 0.628

Gnomad4 NFE AF: 0.643

Gnomad4 OTH AF: 0.734

Alfa AF: 0.662 Hom.: 65691

Bravo AF: 0.711

Asia WGS AF: 0.783 AC: 2723 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.13
DANN	Benign	0.32

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28092; hg19: chr5-102149795;