rs199475619

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3PP4PM3PM2

This summary comes from the ClinGen Evidence Repository: This c.157C>T (p.Arg53Cys) variant in PAH was reported in trans with pathogenic variant p.Arg158Gln in 1 patient with PAH deficiency (324 uMol/L Phe) (PMID:28982351). This variant was found at an amino acid residue where p.Arg53His, a missense variant of uncertain significance, has been seen before. Computational evidence for this missense variant supports a deleterious effect (REVEL=0.766). This variant is found at an extremely low frequency in gnomAD and ExAC (MAF=0.00012), and absent from 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229445/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:5U:2O:1

Conservation

PhyloP100: 2.96

Publications

4 publications found

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]

PAH Gene-Disease associations (from GenCC):

phenylketonuria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
classic phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
maternal phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild hyperphenylalaninemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PAH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.157C>T	p.Arg53Cys	missense	Exon 2 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.157C>T	p.Arg53Cys	missense	Exon 3 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAH	ENST00000553106.6	TSL:1 MANE Select	c.157C>T	p.Arg53Cys	missense	Exon 2 of 13	ENSP00000448059.1	P00439
PAH	ENST00000549111.5	TSL:1	n.253C>T		non_coding_transcript_exon	Exon 2 of 6
PAH	ENST00000906695.1		c.157C>T	p.Arg53Cys	missense	Exon 2 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251390

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000460

AC:

AN:

1456616

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

725060

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.000128

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

1107318

Other (OTH)

AF:

0.0000997

AC:

AN:

60202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41422

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000305

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Phenylketonuria (4)

not provided (2)

not specified (1)

PAH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

Eigen

Benign

0.088

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

0.91

MutationAssessor

Uncertain

2.1

PhyloP100

3.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.011

Polyphen

0.040

Vest4

0.79

MutPred

0.85

Gain of catalytic residue at L54 (P = 0.0174)

MVP

0.95

MPC

0.038

ClinPred

0.32

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.78

Mutation Taster

=8/92

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over