rs77958223

Positions:

• chr12-102855309-T-A
• chr12-102855309-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_Supporting PP3_Moderate PM5 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.533A>T (p.Glu178Val) variant in PAH has not been reported in the literature/in a patient to our knowledge. This variant is absent in population databases. Computational evidence support a deleterious effect (REVEL= 0.866. Functional studies of this variant have been reported to BioPKU: mutant in vitro expression in COS cells reportedly had 18% enzyme activity as compared to wild type. Another missense change at this amino acid (p.Glu178Gly) is classified as pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PM2_supporting, PM5, PP3_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229611/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH ENST00000553106.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.25

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 6 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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.533A>T	p.Glu178Val	missense_variant	6/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.533A>T	p.Glu178Val	missense_variant	7/14		NP_001341233.1
PAH	XM_017019370.2	c.533A>T	p.Glu178Val	missense_variant	6/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.533A>T	p.Glu178Val	missense_variant	6/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5	n.629A>T		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7	c.518A>T	p.Glu173Val	missense_variant	7/14	5		ENSP00000303500
PAH	ENST00000551988.5	n.554A>T		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.36	B;.
Vest4		0.81
MutPred		0.88		Loss of disorder (P = 0.0067);.;
MVP		0.97
MPC		0.036
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs77958223; hg19: chr12-103249087;