5-102946885-C-T

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.575C>T(p.Pro192Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,593,086 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (109 hom.)
• Consequence: PAM NM_001177306.2 missense, splice_region
• Scores: Splicing: ADA: 0.8225
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.29

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009652853).
• BP6: Variant 5-102946885-C-T is Benign according to our data. Variant chr5-102946885-C-T is described in ClinVar as [Benign]. Clinvar id is 777977.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.575C>T	p.Pro192Leu	missense_variant, splice_region_variant	8/26	ENST00000438793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAM	ENST00000438793.8	c.575C>T	p.Pro192Leu	missense_variant, splice_region_variant	8/26	1	NM_001177306.2	P4

Frequencies

GnomAD3 genomes AF: 0.00671 AC: 1020 AN: 152012 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: 0.000578

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00680 AC: 1690 AN: 248434 Hom.: 10 AF XY: 0.00664 AC XY: 891 AN XY: 134206

Gnomad AFR exome AF: 0.00217

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00460

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.000465

Gnomad FIN exome AF: 0.00274

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.00762

GnomAD4 exome AF: 0.0112 AC: 16161 AN: 1440956 Hom.: 109 Cov.: 26 AF XY: 0.0108 AC XY: 7731 AN XY: 717896

Gnomad4 AFR exome AF: 0.00160

Gnomad4 AMR exome AF: 0.00312

Gnomad4 ASJ exome AF: 0.00447

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.000445

Gnomad4 FIN exome AF: 0.00336

Gnomad4 NFE exome AF: 0.0138

Gnomad4 OTH exome AF: 0.00824

GnomAD4 genome AF: 0.00670 AC: 1020 AN: 152130 Hom.: 8 Cov.: 32 AF XY: 0.00613 AC XY: 456 AN XY: 74364

Gnomad4 AFR AF: 0.00210

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.0116 Hom.: 22

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: 0.00709 AC: 860

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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	0.17
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Benign	0.91
DEOGEN2	Uncertain	0.63	D;.;.;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0097	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Benign	0.051
Sift	Uncertain	0.019	D;D;T;D;D
Sift4G	Uncertain	0.032	D;D;D;D;D
Polyphen		0.55	P;P;P;P;P
Vest4		0.39
MVP		0.59
MPC		0.66
ClinPred		0.040	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Benign	0.36
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: rs78753846; hg19: chr5-102282589; COSMIC: COSV57215110; COSMIC: COSV57215110;