rs35658696

Variant names:

• chr5-103003107-A-G
• rs35658696
• NM_001177306.2:c.1688A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001177306.2(PAM):​c.1688A>G​(p.Asp563Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,599,210 control chromosomes in the GnomAD database, including 1,705 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 0.031 (108 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1597 hom.)
• Consequence: PAM NM_001177306.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.29

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008397847).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0311 (4731/152258) while in subpopulation NFE AF = 0.0496 (3370/67996). AF 95% confidence interval is 0.0482. There are 108 homozygotes in GnomAd4. There are 2277 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 108 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAM	NM_001177306.2	c.1688A>G	p.Asp563Gly	missense_variant	Exon 17 of 26	ENST00000438793.8	NP_001170777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAM	ENST00000438793.8	c.1688A>G	p.Asp563Gly	missense_variant	Exon 17 of 26	1	NM_001177306.2	ENSP00000396493.3

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4730 AN: 152140 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.00835

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0566

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.0267

GnomAD2 exomes AF: 0.0312 AC: 7821 AN: 250674 AF XY: 0.0317

Gnomad AFR exome AF: 0.00844

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0609

Gnomad NFE exome AF: 0.0459

Gnomad OTH exome AF: 0.0324

GnomAD4 exome AF: 0.0434 AC: 62784 AN: 1446952 Hom.: 1597 Cov.: 27 AF XY: 0.0424 AC XY: 30587 AN XY: 720872

Gnomad4 AFR exome AF: 0.00713 AC: 237 AN: 33220

Gnomad4 AMR exome AF: 0.0114 AC: 507 AN: 44636

Gnomad4 ASJ exome AF: 0.00365 AC: 95 AN: 26028

Gnomad4 EAS exome AF: 0.0000253 AC: 1 AN: 39588

Gnomad4 SAS exome AF: 0.0186 AC: 1599 AN: 85948

Gnomad4 FIN exome AF: 0.0594 AC: 3169 AN: 53364

Gnomad4 NFE exome AF: 0.0500 AC: 54891 AN: 1098518

Gnomad4 Remaining exome AF: 0.0367 AC: 2201 AN: 59900

GnomAD4 genome AF: 0.0311 AC: 4731 AN: 152258 Hom.: 108 Cov.: 32 AF XY: 0.0306 AC XY: 2277 AN XY: 74460

Gnomad4 AFR AF: 0.00833 AC: 0.00832531 AN: 0.00832531

Gnomad4 AMR AF: 0.0157 AC: 0.0156945 AN: 0.0156945

Gnomad4 ASJ AF: 0.00403 AC: 0.00403226 AN: 0.00403226

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.0141 AC: 0.0140845 AN: 0.0140845

Gnomad4 FIN AF: 0.0566 AC: 0.0565718 AN: 0.0565718

Gnomad4 NFE AF: 0.0496 AC: 0.0495617 AN: 0.0495617

Gnomad4 OTH AF: 0.0260 AC: 0.0259924 AN: 0.0259924

Alfa AF: 0.0405 Hom.: 488

Bravo AF: 0.0268

TwinsUK AF: 0.0545 AC: 202

ALSPAC AF: 0.0579 AC: 223

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.0493 AC: 424

ExAC AF: 0.0322 AC: 3908

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.0387

EpiControl AF: 0.0416

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
MetaRNN	Benign	0.0084	T;T;T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.1	M;M;.;M;M
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.4	D;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D
Polyphen		0.99	D;D;D;D;D
Vest4		0.35
MPC		0.75
ClinPred		0.016	T
GERP RS		5.9
Varity_R		0.47
gMVP		0.82
Mutation Taster		=279/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs35658696; hg19: chr5-102338811; COSMIC: COSV57213274; COSMIC: COSV57213274;