rs199475620

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4PM4PM3PS3PM2

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PP4: Phe>120 umol/L with PKU (PMID:25456745); PM3: In trans with: c.842+2T>A (P, ClinGen) (PMID:25456745); PS3: 0% in BioPKU; PM2: Extremely low frequency. ExAC MAF=0.00012; PM4: In frame deletion. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4, PM3, PS3, PM2, PM4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229490/MONDO:0009861/006

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PAH
NM_000277.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:8O:3

Conservation

PhyloP100: 8.90

Publications

20 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:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS3

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

PM2

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

PM3

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

PM4

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.208_210delTCT	p.Ser70del	conservative_inframe_deletion	Exon 3 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.208_210delTCT	p.Ser70del	conservative_inframe_deletion	Exon 4 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.208_210delTCT	p.Ser70del	conservative_inframe_deletion	Exon 3 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.304_306delTCT		non_coding_transcript_exon	Exon 3 of 6
	PAH	ENST00000906695.1		c.208_210delTCT	p.Ser70del	conservative_inframe_deletion	Exon 3 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

1

AN:

152068

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

3

AN:

251342

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000205

AC:

3

AN:

1461628

Hom.:

0

AF XY:

0.00000275

AC XY:

2

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33472

American (AMR)

AF:

0.0000224

AC:

1

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

1

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

0

AN:

1111834

Other (OTH)

AF:

0.0000166

AC:

1

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0

1

1

2

2

3

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

2

4

6

8

10

<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:

0.00000657

AC:

1

AN:

152186

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41514

American (AMR)

AF:

0.00

AC:

0

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

1

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

0

AN:

68026

Other (OTH)

AF:

0.00

AC:

0

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

0

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

8

-

-

Phenylketonuria (8)

-

-

-

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.9

Mutation Taster

=10/90

disease causing (ClinVar)

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

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Other links and lift over

dbSNP: rs62642094; hg19: chr12-103288654; API