rs62642928

Variant names:

• chr12-102912838-G-A
• rs62642928
• NM_000277.3:c.121C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM3 PS3 PP4_Moderate PM2

This summary comes from the ClinGen Evidence Repository: The c.121C>T (p.Leu41Phe) variant in PAH has been reported in 2 individuals with mild PKU (BH4 deficiency excluded). (PMID:21147011, 8268925). This variant is absent in population databases. This variant has 10% enzyme activity PMID:21953985. This variant was detected with IVS10-11G>A (PMID:21147011) and R261Q (PMID:8268925)). Computational prediction tools are conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229401/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 4.58
• Publications: 6 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

ACMG classification

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

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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.121C>T	p.Leu41Phe	missense	Exon 2 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.121C>T	p.Leu41Phe	missense	Exon 3 of 14	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.121C>T	p.Leu41Phe	missense	Exon 2 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.217C>T		non_coding_transcript_exon	Exon 2 of 6
	PAH	ENST00000906695.1		c.121C>T	p.Leu41Phe	missense	Exon 2 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.89		Gain of methylation at K42 (P = 0.0383)
MVP		0.99
MPC		0.23
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.75
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs62642928; hg19: chr12-103306616;