5-102867275-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001177306.2(PAM):c.92T>A(p.Phe31Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00187 in 1,599,074 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0087 (19 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (14 hom.)
• Consequence: PAM NM_001177306.2 missense, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.54

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042791665).
• BP6: Variant 5-102867275-T-A is Benign according to our data. Variant chr5-102867275-T-A is described in ClinVar as [Benign]. Clinvar id is 780546.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00867 (1321/152308) while in subpopulation AFR AF= 0.0282 (1170/41556). AF 95% confidence interval is 0.0268. There are 19 homozygotes in gnomad4. There are 624 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAM	NM_001177306.2	c.92T>A	p.Phe31Tyr	missense_variant, splice_region_variant	3/26	ENST00000438793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAM	ENST00000438793.8	c.92T>A	p.Phe31Tyr	missense_variant, splice_region_variant	3/26	1	NM_001177306.2	P4

Frequencies

GnomAD3 genomes AF: 0.00865 AC: 1317 AN: 152190 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00242 AC: 606 AN: 250484 Hom.: 8 AF XY: 0.00182 AC XY: 247 AN XY: 135396

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000441

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00115 AC: 1671 AN: 1446766 Hom.: 14 Cov.: 26 AF XY: 0.000998 AC XY: 719 AN XY: 720760

Gnomad4 AFR exome AF: 0.0296

Gnomad4 AMR exome AF: 0.00289

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000583

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000343

Gnomad4 OTH exome AF: 0.00276

GnomAD4 genome AF: 0.00867 AC: 1321 AN: 152308 Hom.: 19 Cov.: 33 AF XY: 0.00838 AC XY: 624 AN XY: 74468

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.00725

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00162 Hom.: 1

Bravo AF: 0.00986

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0281 AC: 124

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00281 AC: 341

Asia WGS AF: 0.000867 AC: 3 AN: 3476

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

Aug 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	21
Dann	Benign	0.94
DEOGEN2	Benign	0.0050	T;T;.;T;.;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.044
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0043	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.96	D;D;D;D;D;D;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.47	N;N;N;N;N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.62	T;T;T;T;T;T;T;T
Sift4G	Benign	0.84	T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0	.;.;.;B;B;B;B;B
Vest4		0.30, 0.32, 0.30, 0.29
MVP		0.51
MPC		0.25
ClinPred		0.0077	T
GERP RS		4.5
Varity_R		0.095
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs114014768; hg19: chr5-102202979;