12-102877457-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3PM3PM2_SupportingPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000277.3: c.441+5G>A variant in PAH is an intronic variant that is predicted by SpliceAI to alter splicing (SpliceAI score 0.91, >0.2 cutoff for PP3). c.441+5G>A has a Pop max allele frequency of [8.498e-7] for [ENF] chromosomes by gnomAD v4.1.0, which is lower than the ClinGen PAH threshold (≤ 0.0002) and therefore meets PM2_Supporting. It has been observed in individuals with phenylalanine hydroxylase deficiency in presumed trans (phase confirmed) with other pathogenic variants, including with p.Arg158Gln (ClinVar ID: 587) in one individual (PMID:18321666) and with p.Val388Met (ClinVar ID 619) in 8 individuals (PMID:32668217) (PM3_VeryStrong). It has been observed in at least one classic PKU patient with BH4 deficiency excluded (PMID:18321666; PP4_moderate). 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: PM2_Supporting, PM3_VeryStrong, PP3, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020788/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PAH
NM_000277.3 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P: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), G2P, ClinGen, Myriad Women’s Health
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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
PAH	NM_000277.3 link	c.441+5G>A	splice_region_variant, intron_variant	Intron 4 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 link	c.441+5G>A	splice_region_variant, intron_variant	Intron 5 of 13		NP_001341233.1
PAH	XM_017019370.2 link	c.441+5G>A	splice_region_variant, intron_variant	Intron 4 of 6		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.808-2422C>T	intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.441+5G>A		splice_region_variant, intron_variant	Intron 4 of 12	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458196

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725660

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33402

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108646

Other (OTH)

AF:

0.00

AC:

AN:

60256

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:1

Nov 17, 2024

ClinGen PAH Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000277.3: c.441+5G>A variant in PAH is an intronic variant that is predicted by SpliceAI to alter splicing (SpliceAI score 0.91, >0.2 cutoff for PP3). c.441+5G>A has a Pop max allele frequency of [8.498e-7] for [ENF] chromosomes by gnomAD v4.1.0, which is lower than the ClinGen PAH threshold (≤ 0.0002) and therefore meets PM2_Supporting. It has been observed in individuals with phenylalanine hydroxylase deficiency in presumed trans (phase confirmed) with other pathogenic variants, including with p.Arg158Gln (ClinVar ID: 587) in one individual (PMID: 18321666) and with p.Val388Met (ClinVar ID 619) in 8 individuals (PMID: 32668217) (PM3_VeryStrong). It has been observed in at least one classic PKU patient with BH4 deficiency excluded (PMID: 18321666; PP4_moderate). 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: PM2_Supporting, PM3_VeryStrong, PP3, PP4_Moderate.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

7.3

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over