5-102959982-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001177306.2(PAM):​c.1013T>A​(p.Phe338Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PAM
NM_001177306.2 missense

Scores

1
13
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PAMNM_001177306.2 linkc.1013T>A p.Phe338Tyr missense_variant 13/26 ENST00000438793.8 NP_001170777.1 P19021-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PAMENST00000438793.8 linkc.1013T>A p.Phe338Tyr missense_variant 13/261 NM_001177306.2 ENSP00000396493.3 P19021-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250892
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135580
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460360
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726550
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 28, 2024The c.1013T>A (p.F338Y) alteration is located in exon 12 (coding exon 12) of the PAM gene. This alteration results from a T to A substitution at nucleotide position 1013, causing the phenylalanine (F) at amino acid position 338 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
0.060
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
T;.;.;.;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.93
D;D;D;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D
MetaSVM
Uncertain
-0.087
T
MutationAssessor
Benign
1.4
L;L;L;L;L
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-1.6
N;N;N;N;N
REVEL
Uncertain
0.59
Sift
Uncertain
0.017
D;D;D;D;D
Sift4G
Benign
0.14
T;T;T;T;T
Polyphen
1.0
D;D;D;D;D
Vest4
0.83
MutPred
0.74
Gain of phosphorylation at F338 (P = 0.0073);Gain of phosphorylation at F338 (P = 0.0073);Gain of phosphorylation at F338 (P = 0.0073);Gain of phosphorylation at F338 (P = 0.0073);Gain of phosphorylation at F338 (P = 0.0073);
MVP
0.75
MPC
0.69
ClinPred
0.95
D
GERP RS
5.6
Varity_R
0.33
gMVP
0.79

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1255565504; hg19: chr5-102295686; API