rs62508737

Variant names:

• chr12-102843644-A-C
• rs62508737
• NM_000277.3:c.1199+2T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-102843644-A-C
• chr12-102843644-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

This summary comes from the ClinGen Evidence Repository: The c.1199+2T>G variant in PAH occurs within the canonical splice donor of intron 11. It is predicted to cause skipping of biologically-relevant exon 11, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. This variant may be reported in the literature (PMID:25863075), but is unavailable for evaluation. Sequence analysis of a PKU mouse model with this variant revealed two cryptic splice donor sites, upstream and downstream of the wild-type splice site (PMID:11161825). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PVS1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA386493122/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAH ENST00000553106.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.50
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000553106.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.1199+2T>G		splice_donor intron	N/A	NP_000268.1
	PAH	NM_001354304.2		c.1199+2T>G		splice_donor intron	N/A	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.1199+2T>G		splice_donor intron	N/A	ENSP00000448059.1
	PAH	ENST00000307000.7	TSL:5	c.1184+2T>G		splice_donor intron	N/A	ENSP00000303500.2
	PAH	ENST00000635477.1	TSL:5	c.302+2T>G		splice_donor intron	N/A	ENSP00000489230.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Phenylketonuria (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.5
GERP RS		5.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: -15
DS_DL_spliceai		0.64		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62508737; hg19: chr12-103237422;