12-102852830-A-T

Variant names:

• chr12-102852830-A-T
• rs62508722
• NM_000277.3:c.827T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM5 PM3 PM2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.827T>A (p.Met276Lys) variant in PAH is absent from population databases, and found in the same codon as a previously reported pathogenic variant (p.Met276Val). It has been identified in trans with a known pathogenic variant (I95del), in which a defect of BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID:25894915). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229795/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 7.45
• Publications: 13 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 8 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.
• PM5: 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.827T>A	p.Met276Lys	missense	Exon 7 of 13	NP_000268.1
	PAH	NM_001354304.2		c.827T>A	p.Met276Lys	missense	Exon 8 of 14	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.827T>A	p.Met276Lys	missense	Exon 7 of 13	ENSP00000448059.1
	PAH	ENST00000307000.7	TSL:5	c.812T>A	p.Met271Lys	missense	Exon 8 of 14	ENSP00000303500.2
	PAH	ENST00000549247.6	TSL:2	n.586T>A		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	Benign	0.27
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.97	D
Eigen	Benign	0.086
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.78
Sift	Benign	0.081	T
Sift4G	Benign	0.078	T
Polyphen		0.0040	B
Vest4		0.79
MutPred		0.88		Gain of methylation at M276 (P = 0.0202)
MVP		0.97
MPC		0.041
ClinPred		0.90	D
GERP RS		5.7
PromoterAI		0.031	Neutral
Varity_R		0.92
gMVP		0.97
Mutation Taster		=3/97	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: rs62508722; hg19: chr12-103246608;