chr12-102877459-C-G

Variant names:

• chr12-102877459-C-G
• rs62508642
• NM_000277.3:c.441+3G>C

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3 PP4_Moderate PM2

This summary comes from the ClinGen Evidence Repository: This c.441+3G>C (IVS4+3G>C) variant was documented at least 7 times in patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID:28982351, 5894915, 30050108). This variant was also documented in two patients homozygous for the c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic PKU (PMID:30050108). This variant was documented 12 times in patients with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID:26503515, 16256386, 23932990). This variant is absent from the population databases ExAC and gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very strong, PM2, PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229546/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAH NM_000277.3 splice_region, intron
• Scores: Splicing: ADA: 0.9972
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 1.83
• Publications: 4 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), ClinGen, Myriad Women’s Health, G2P
• 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

LOC124902999 (HGNC:):

ACMG classification

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.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.441+3G>C		splice_region intron	N/A	NP_000268.1	P00439
	PAH	NM_001354304.2		c.441+3G>C		splice_region intron	N/A	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.441+3G>C		splice_region intron	N/A	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.537+3G>C		splice_region intron	N/A
	PAH	ENST00000550978.6	TSL:2	c.426G>C	p.Val142Val	synonymous	Exon 4 of 4	ENSP00000489016.1	A0A0U1RQI3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: 3

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

Other links and lift over

dbSNP: rs62508642; hg19: chr12-103271237;