12-102877457-C-T

Variant names:

• chr12-102877457-C-T
• rs62507321
• NM_000277.3:c.441+5G>A

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_Moderate PP3 PM3 PM2_Supporting

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

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]

LOC124902999 (HGNC:):

ACMG classification

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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.441+5G>A		splice_region_variant, intron_variant	Intron 4 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.441+5G>A		splice_region_variant, intron_variant	Intron 5 of 13		NP_001341233.1
PAH	XM_017019370.2	c.441+5G>A		splice_region_variant, intron_variant	Intron 4 of 6		XP_016874859.1
LOC124902999	XR_007063428.1	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	c.441+5G>A		splice_region_variant, intron_variant	Intron 4 of 12	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458196 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725660

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

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	18
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

Other links and lift over

dbSNP: rs62507321; hg19: chr12-103271235;