Variant 12-102877457-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 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

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 links:

PAH (HGNC:):

PAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.441+5G>A	splice_region_variant, intron_variant	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.441+5G>A	splice_region_variant, intron_variant		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.441+5G>A	splice_region_variant, intron_variant		XP_016874859.1
LOC124902999	XR_007063428.1 linkuse as main transcript	n.808-2422C>T	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.441+5G>A		splice_region_variant, intron_variant		1	NM_000277.3	ENSP00000448059.1		P00439

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Nov 17, 2024

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

DANN

Benign

0.92

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over