chr12-102855176-A-C

Variant names:

• chr12-102855176-A-C
• rs1263259211
• NM_000277.3:c.666T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_000277.3(PAH):​c.666T>G​(p.Asp222Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D222G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.39

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102855177-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794
• PP5: Variant 12-102855176-A-C is Pathogenic according to our data. Variant chr12-102855176-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1496717.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.666T>G	p.Asp222Glu	missense_variant	Exon 6 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.666T>G	p.Asp222Glu	missense_variant	Exon 7 of 14		NP_001341233.1
PAH	XM_017019370.2	c.666T>G	p.Asp222Glu	missense_variant	Exon 6 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.666T>G	p.Asp222Glu	missense_variant	Exon 6 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.762T>G		non_coding_transcript_exon_variant	Exon 6 of 6	1
PAH	ENST00000307000.7	c.651T>G	p.Asp217Glu	missense_variant	Exon 7 of 14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.*103T>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Phenylketonuria Pathogenic:1

Feb 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 222 of the PAH protein (p.Asp222Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PAH-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. This variant disrupts the p.Asp222 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9429153, 10598814). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.097	T;T
Polyphen		0.026	B;.
Vest4		0.62
MutPred		0.73		Gain of solvent accessibility (P = 0.1014);.;
MVP		0.91
MPC		0.072
ClinPred		0.96	D
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.71
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1263259211; hg19: chr12-103248954;