12-102877461-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP4PM3PVS1PM2PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.441+1G>A variant in PAH is a canonical splice variant in +1 splice site (exon 3/4 junction) in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (PVS1; see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria). In addition, the variant has been previously shown by RT-PCR analysis to alter RNA splicing (PS3_Supporting; PMID:8535445). It is ultra-rare (highest observed population frequency 0.00001, with zero homozygotes, in gnomAD Non-Finnish European subpopulation), well under the PAH-specific frequency cutoff of 0.0002 (PM2). It has been found in multiple probands with classic PKU (e.g., PMID:7726156, 8535445, 16256386, 17096675, 20187763, 22112818, 24350308, 23430918, 23764561, 8535445), although BH4 deficiency does not appear to have been formally excluded (PP4), including in trans with the Clinvar-Pathogenic R408W allele (PMID:22112818) (PM3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229545/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PAH
NM_000277.3 splice_donor, intron

Scores

4

2

Splicing: ADA: 1.000

2

Clinical Significance

Pathogenic reviewed by expert panel P:12O:1

Conservation

PhyloP100: 7.28

Publications

6 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 14 ACMG points.

PVS1

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

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.

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.441+1G>A		splice_donor intron	N/A	NP_000268.1	P00439
	PAH	NM_001354304.2		c.441+1G>A		splice_donor intron	N/A	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.441+1G>A		splice_donor intron	N/A	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.537+1G>A		splice_donor intron	N/A
	PAH	ENST00000550978.6	TSL:2	c.424G>A	p.Val142Met	missense	Exon 4 of 4	ENSP00000489016.1	A0A0U1RQI3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152092

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

1

AN:

251482

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

4

AN:

1459438

Hom.:

0

Cov.:

31

AF XY:

0.00000413

AC XY:

3

AN XY:

726224

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33428

American (AMR)

AF:

0.00

AC:

0

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000360

AC:

4

AN:

1109766

Other (OTH)

AF:

0.00

AC:

0

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.0000131

AC:

2

AN:

152092

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41426

American (AMR)

AF:

0.00

AC:

0

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

2

AN:

68034

Other (OTH)

AF:

0.00

AC:

0

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.0000295

Hom.:

0

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000116

AC:

1

ExAC

AF:

0.00000824

AC:

1

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

8

-

-

Phenylketonuria (8)

3

-

-

not provided (4)

1

-

-

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

D

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

29

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.94

D

PhyloP100

7.3

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.91

Position offset: 1

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: rs62517166; hg19: chr12-103271239; COSMIC: COSV61020073; COSMIC: COSV61020073; API