rs249496

Positions:

• chr5-102865886-C-G
• chr5-102865886-C-T

Variant summary

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

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17

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=-0.78).
• 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/exons	MANE	Protein	UniProt
PAM	NM_001177306.2	c.-310C>G		5_prime_UTR_variant	2/26	ENST00000438793.8	NP_001170777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAM	ENST00000438793.8	c.-310C>G		5_prime_UTR_variant	2/26	1	NM_001177306.2	ENSP00000396493	P4

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77983 AN: 151894 Hom.: 21840 Cov.: 32

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.: 0 AF XY: 0.440 AC XY: 38536 AN XY: 87634

Gnomad4 AFR exome AF: 0.714

Gnomad4 AMR exome AF: 0.583

Gnomad4 ASJ exome AF: 0.452

Gnomad4 EAS exome AF: 0.607

Gnomad4 SAS exome AF: 0.655

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.399

Gnomad4 OTH exome AF: 0.453

GnomAD4 genome AF: 0.514 AC: 78116 AN: 152010 Hom.: 21910 Cov.: 32 AF XY: 0.514 AC XY: 38190 AN XY: 74312

Gnomad4 AFR AF: 0.723

Gnomad4 AMR AF: 0.544

Gnomad4 ASJ AF: 0.457

Gnomad4 EAS AF: 0.622

Gnomad4 SAS AF: 0.663

Gnomad4 FIN AF: 0.293

Gnomad4 NFE AF: 0.401

Gnomad4 OTH AF: 0.509

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	13
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs249496; hg19: chr5-102201590;