NM_000277.3:c.1A>T

Variant names:

• chr12-102917130-T-A
• rs62514891
• NM_000277.3:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP4 PM3 PVS1 PM2

This summary comes from the ClinGen Evidence Repository: The PAH:p.M1L variant is a predicted start-lost variant in the canonical transcript of PAH (ENST00000553106); There are no other PAH RefSeq transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID:9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant was reported in trans with the pathogenic variant p.Arg241His (PM3) in 1 Mexican proband with mild PKU (PMID:24941924; PP4). It is absent from control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PVS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229482/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 initiator_codon
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 3.30
• Publications: 28 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 13 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.
• 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.1A>T	p.Met1?	initiator_codon	Exon 1 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.1A>T	p.Met1?	initiator_codon	Exon 2 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.1A>T	p.Met1?	initiator_codon	Exon 1 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.97A>T		non_coding_transcript_exon	Exon 1 of 6
	PAH	ENST00000307000.7	TSL:5	c.-147A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000303500.2	J3KND8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.040
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.90	D
PhyloP100		3.3
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.61
Sift	Benign	0.60	T
Sift4G	Benign	1.0	T
Polyphen		0.17	B
Vest4		0.98
MutPred		1.0		Loss of sheet (P = 0.1158)
MVP		0.94
ClinPred		0.53	D
GERP RS		5.2
PromoterAI		-0.092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.60
Mutation Taster		=3/197	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: rs62514891; hg19: chr12-103310908;