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NM_000277.2(PAH):c.169G>A (p.Glu57Lys)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP4_ModeratePM3_Supporting

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ESP MAF=0.00012.; PP4_Moderate: Detected in a patient with mild HPA. Assessment of the PAH, PTS, and QDPR genes was performed. (PMID:21147011); PM3-supporting: Detected with V388M, pathogenic in ClinVar, but parental testing not performed. (PMID:21147011). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220578/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PAH
XM_017019370.2 missense, splice_region

Scores

6
5
8
Splicing: ADA: 0.9996
2

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:3

Conservation

PhyloP100: 5.27
Variant links:
Genes affected
PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
PM3
PP4

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PAHNM_000277.3 linkuse as main transcriptc.169G>A p.Glu57Lys missense_variant, splice_region_variant 3/13 ENST00000553106.6
LOC124902999XR_007063428.1 linkuse as main transcriptn.863-9780C>T intron_variant, non_coding_transcript_variant
PAHNM_001354304.2 linkuse as main transcriptc.169G>A p.Glu57Lys missense_variant, splice_region_variant 4/14
PAHXM_017019370.2 linkuse as main transcriptc.169G>A p.Glu57Lys missense_variant, splice_region_variant 3/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PAHENST00000553106.6 linkuse as main transcriptc.169G>A p.Glu57Lys missense_variant, splice_region_variant 3/131 NM_000277.3 P1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152048
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250312
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135352
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:
0.00000883
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000206
AC:
30
AN:
1459598
Hom.:
0
Cov.:
29
AF XY:
0.0000193
AC XY:
14
AN XY:
726264
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000216
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152048
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74254
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 29, 2015- -
Likely pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2019- -
Phenylketonuria Uncertain:2
Uncertain significance, reviewed by expert panelcurationClinGen PAH Variant Curation Expert PanelApr 26, 2019PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ESP MAF=0.00012.; PP4_Moderate: Detected in a patient with mild HPA. Assessment of the PAH, PTS, and QDPR genes was performed. (PMID:21147011); PM3-supporting: Detected with V388M, pathogenic in ClinVar, but parental testing not performed. (PMID:21147011). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_supporting). -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 03, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
D;T;T;D
Eigen
Benign
0.019
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Pathogenic
0.65
D
MetaRNN
Uncertain
0.58
D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Benign
1.4
L;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-1.5
N;N;N;N
REVEL
Uncertain
0.51
Sift
Benign
0.32
T;T;T;T
Sift4G
Benign
0.64
T;T;T;.
Polyphen
0.0050
B;.;.;.
Vest4
0.66
MVP
0.94
MPC
0.033
ClinPred
0.32
T
GERP RS
6.2
Varity_R
0.84
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.84
SpliceAI score (max)
0.64
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.64
Position offset: -3

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: rs140945592; hg19: chr12-103288696; COSMIC: COSV61017958; API