12-102917128-C-T

Variant names:

• chr12-102917128-C-T
• rs62514893
• NM_000277.3:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PP1 PS2_Moderate PM3_Strong PP4_Moderate PVS1 PM2

This summary comes from the ClinGen Evidence Repository: The c.3G>A (p.Met1Ile) variant is a null variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other 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 has been detected in multiple patients with PKU, BH4 deficiency excluded. PMID:1301947, 23514811 (PP4_Moderate). This variant is absent in population databases (PM2). This variant was detected in trans with pathogenic variants IVS12+1G>A (PMID:1301947) and p.F55L (27121329) (PM3_Strong). This variant has been detected de novo (PS2_moderate; PMID:1301947), and in affected siblings (PP1; 23514811) In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PVS1, PM2, PP4_Moderate, PS2_moderate, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229532/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 3.26
• Publications: 15 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 19 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS2: 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.
• PP1: 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.3G>A	p.Met1?	start_lost	Exon 1 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.3G>A	p.Met1?	start_lost	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.3G>A	p.Met1?	start_lost	Exon 1 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.99G>A		non_coding_transcript_exon	Exon 1 of 6
	PAH	ENST00000906695.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		3.3
PROVEAN	Benign	-0.58	N
REVEL	Uncertain	0.62
Sift	Benign	0.036	D
Sift4G	Benign	0.15	T
Polyphen		0.53	P
Vest4		0.97
MutPred		1.0		Gain of sheet (P = 0.039)
MVP		0.97
ClinPred		0.98	D
GERP RS		5.2
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.66
Mutation Taster		=4/196	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: rs62514893; hg19: chr12-103310906;