5-102974426-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001177306.2(PAM):c.1473A>C(p.Glu491Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,611,724 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (8 hom., cov: 32)
  • Exomes 𝑓: 0.012 (115 hom.)
• Consequence: PAM NM_001177306.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.357

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047815144).
• BP6: Variant 5-102974426-A-C is Benign according to our data. Variant chr5-102974426-A-C is described in ClinVar as [Benign]. Clinvar id is 777979.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAM	NM_001177306.2	c.1473A>C	p.Glu491Asp	missense_variant	15/26	ENST00000438793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAM	ENST00000438793.8	c.1473A>C	p.Glu491Asp	missense_variant	15/26	1	NM_001177306.2	P4

Frequencies

GnomAD3 genomes AF: 0.00666 AC: 1014 AN: 152202 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00701 AC: 1744 AN: 248758 Hom.: 8 AF XY: 0.00689 AC XY: 926 AN XY: 134468

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00317

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000494

Gnomad FIN exome AF: 0.00285

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.00760

GnomAD4 exome AF: 0.0116 AC: 16946 AN: 1459404 Hom.: 115 Cov.: 30 AF XY: 0.0112 AC XY: 8111 AN XY: 725996

Gnomad4 AFR exome AF: 0.00159

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00450

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00343

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.00874

GnomAD4 genome AF: 0.00666 AC: 1014 AN: 152320 Hom.: 8 Cov.: 32 AF XY: 0.00607 AC XY: 452 AN XY: 74494

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.0116 Hom.: 24

Bravo AF: 0.00681

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0142 AC: 122

ExAC AF: 0.00741 AC: 899

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0122

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	14
Dann	Benign	0.96
DEOGEN2	Benign	0.21	T;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.80	T;T;T;T
MetaRNN	Benign	0.0048	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L;L;L
MutationTaster	Benign	1.0	D;D;N;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.70	N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.39	T;T;T;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.18
MutPred		0.25		Loss of catalytic residue at E491 (P = 0.0762);Loss of catalytic residue at E491 (P = 0.0762);Loss of catalytic residue at E491 (P = 0.0762);Loss of catalytic residue at E491 (P = 0.0762);
MVP		0.56
MPC		0.14
ClinPred		0.0051	T
GERP RS		-1.4
Varity_R		0.084
gMVP		0.37

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: rs61736661; hg19: chr5-102310130;