5-102867328-G-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.145G>C(p.Val49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,600,974 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0093 (5 hom., cov: 32)
  • Exomes 𝑓: 0.013 (152 hom.)
• Consequence: PAM NM_001177306.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.10

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=0.004789859).
• BP6: Variant 5-102867328-G-C is Benign according to our data. Variant chr5-102867328-G-C is described in ClinVar as [Benign]. Clinvar id is 773172.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAM	NM_001177306.2	c.145G>C	p.Val49Leu	missense_variant	3/26	ENST00000438793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAM	ENST00000438793.8	c.145G>C	p.Val49Leu	missense_variant	3/26	1	NM_001177306.2	P4

Frequencies

GnomAD3 genomes AF: 0.00928 AC: 1411 AN: 152088 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00372

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00856 AC: 2150 AN: 251190 Hom.: 24 AF XY: 0.00856 AC XY: 1162 AN XY: 135776

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.00429

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.0128 AC: 18566 AN: 1448768 Hom.: 152 Cov.: 26 AF XY: 0.0126 AC XY: 9063 AN XY: 721646

Gnomad4 AFR exome AF: 0.00256

Gnomad4 AMR exome AF: 0.00439

Gnomad4 ASJ exome AF: 0.00469

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000977

Gnomad4 FIN exome AF: 0.0173

Gnomad4 NFE exome AF: 0.0150

Gnomad4 OTH exome AF: 0.00983

GnomAD4 genome AF: 0.00926 AC: 1410 AN: 152206 Hom.: 5 Cov.: 32 AF XY: 0.00919 AC XY: 684 AN XY: 74408

Gnomad4 AFR AF: 0.00371

Gnomad4 AMR AF: 0.00707

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0180

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.0117 Hom.: 5

Bravo AF: 0.00811

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0114 AC: 98

ExAC AF: 0.00801 AC: 972

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0139

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

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	16
Dann	Benign	0.96
DEOGEN2	Benign	0.089	T;.;T;.;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D
MetaRNN	Benign	0.0048	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N
REVEL	Benign	0.058
Sift	Benign	0.058	T;T;T;D;D;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T
Polyphen		0.0, 0.0020	.;.;B;B;B;B;B
Vest4		0.33, 0.33, 0.33, 0.34, 0.34
MutPred		0.18		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.48
MPC		0.15
ClinPred		0.0095	T
GERP RS		3.9
Varity_R		0.044
gMVP		0.42

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: rs2230458; hg19: chr5-102203032; COSMIC: COSV99053335; COSMIC: COSV99053335;