12-102877457-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP3PS3PM3_StrongPM2PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.441+5G>T variant in PAH has been reported on >17 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID:17935162; PMID:23514811). This variant has an extremely low allele frequency (0.00002886) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org). This variant was detected in trans with IVS10-11g>a and p.V388M (Pathogenic in ClinVar) (PM3_Strong; PMID:23514811). Computational prediction tools and conservation analysis suggest that the c.441+5G>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Strong LINK:https://erepo.genome.network/evrepo/ui/classification/CA273112/MONDO:0009861/006

Frequency

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

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PAH
NM_000277.3 splice_region, intron

Scores

2

Splicing: ADA: 1.000

2

Clinical Significance

Pathogenic reviewed by expert panel P:16O:1

Conservation

PhyloP100: 7.28

Publications

16 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 13 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.

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.441+5G>T		splice_region intron	N/A	NP_000268.1	P00439
	PAH	NM_001354304.2		c.441+5G>T		splice_region 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+5G>T		splice_region intron	N/A	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.537+5G>T		splice_region intron	N/A
	PAH	ENST00000550978.6	TSL:2	c.428G>T	p.Ser143Ile	missense	Exon 4 of 4	ENSP00000489016.1	A0A0U1RQI3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152116

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD2 exomes

AF:

0.0000318

AC:

8

AN:

251488

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

34

AN:

1458196

Hom.:

0

Cov.:

31

AF XY:

0.0000248

AC XY:

18

AN XY:

725660

show subpopulations

African (AFR)

AF:

0.0000299

AC:

1

AN:

33402

American (AMR)

AF:

0.000134

AC:

6

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

2

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000189

AC:

21

AN:

1108646

Other (OTH)

AF:

0.0000664

AC:

4

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0

3

6

9

12

15

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:

152116

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41432

American (AMR)

AF:

0.0000654

AC:

1

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

1

AN:

68042

Other (OTH)

AF:

0.00

AC:

0

AN:

2092

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

Age Distribution

Genome 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

Alfa

AF:

0.0000330

Hom.:

0

Bravo

AF:

0.0000793

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

11

-

-

Phenylketonuria (11)

4

-

-

not provided (5)

1

-

-

PAH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

18

DANN

Benign

0.93

PhyloP100

7.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=0/100

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.91

Position offset: 5

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: rs62507321; hg19: chr12-103271235; API