12-102866662-C-A

Variant names:

• chr12-102866662-C-A
• rs1555205655
• NM_000277.3:c.443G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4_Moderate PM2 PP3 PM3

This summary comes from the ClinGen Evidence Repository: The c.443G>T (p.Gly148Val) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID:27121329, 26503515). This variant is absent in population databases (PM2). This variant was detected in trans with pathogenic variant p.Ser349Pro. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020791/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense, splice_region
• Scores: Splicing: ADA: 0.9763
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 5.24

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]

LOC124902999 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.443G>T	p.Gly148Val	missense_variant, splice_region_variant	Exon 5 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.443G>T	p.Gly148Val	missense_variant, splice_region_variant	Exon 6 of 14		NP_001341233.1
PAH	XM_017019370.2	c.443G>T	p.Gly148Val	missense_variant, splice_region_variant	Exon 5 of 7		XP_016874859.1
LOC124902999	XR_007063428.1	n.807+1435C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.443G>T	p.Gly148Val	missense_variant, splice_region_variant	Exon 5 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.539G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 6	1
PAH	ENST00000307000.7	c.428G>T	p.Gly143Val	missense_variant, splice_region_variant	Exon 6 of 14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.530+10800G>T		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Uncertain:1

Jun 27, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.443G>T (p.Gly148Val) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID: 27121329, 26503515). This variant is absent in population databases (PM2). This variant was detected in trans with pathogenic variant p.Ser349Pro. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.4	H;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.7	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.91		Loss of disorder (P = 0.0436);.;
MVP		0.99
MPC		0.26
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.91
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

Publications

LitVar

Other links and lift over

dbSNP: rs1555205655; hg19: chr12-103260440;