rs62508689

Variant names:

• chr12-102844333-T-C
• rs62508689
• NM_000277.3:c.1065+3A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-102844333-T-C
• chr12-102844333-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP1 PP4 PP3 PM3 PM2

This summary comes from the ClinGen Evidence Repository: The c.1065+3A>G variant in PAH was detected in 2 siblings with an increased serum Phenylalanine level of 365 uM. BH4 deficiency was not assessed/reported. (PMID:8088845) They were compound heterozygous for Y414C. The c.1065+3A>G variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted for this variant in HSF and MaxEnt (Alteration of the WT donor site; activation of an intronic cryptic donor site). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP1, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA212751/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 splice_region, intron
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2 O:1
• Conservation: PhyloP100: 0.172
• 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 7 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.
• PP1: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.1065+3A>G		splice_region intron	N/A	NP_000268.1
	PAH	NM_001354304.2		c.1065+3A>G		splice_region 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.1065+3A>G		splice_region intron	N/A	ENSP00000448059.1
	PAH	ENST00000307000.7	TSL:5	c.1050+3A>G		splice_region intron	N/A	ENSP00000303500.2
	PAH	ENST00000635477.1	TSL:5	c.168+3A>G		splice_region intron	N/A	ENSP00000489230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (3)
1	-	-	Hyperphenylalaninemia (1)
1	-	-	Phenylketonuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.91
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.57		Position offset: 3

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

Other links and lift over

dbSNP: rs62508689; hg19: chr12-103238111;