rs199475567

Variant names:

• chr12-102912791-C-A
• rs199475567
• NM_000277.3:c.168G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102912791-C-A
• chr12-102912791-C-T

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3 PM2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.168G>T (p.Glu56Asp) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded) (PMID:21147011, 23932990, 30050108). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: R243Q (PMID:8019568); R408W and T356X (PMID:21147011); p.V399V, c.442-1G>A, p.I65T, p.R261Q (PMID:30050108). Computational prediction tools and conservation analysis do not agree on the impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229459/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 2.59
• Publications: 8 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: Pathogenic. The variant received 6 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.
• 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.168G>T	p.Glu56Asp	missense splice_region	Exon 2 of 13	NP_000268.1
	PAH	NM_001354304.2		c.168G>T	p.Glu56Asp	missense splice_region	Exon 3 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.168G>T	p.Glu56Asp	missense splice_region	Exon 2 of 13	ENSP00000448059.1
	PAH	ENST00000549111.5	TSL:1	n.264G>T		splice_region non_coding_transcript_exon	Exon 2 of 6
	PAH	ENST00000307000.7	TSL:5	c.153G>T	p.Glu51Asp	missense splice_region	Exon 3 of 14	ENSP00000303500.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.075
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.63
Sift	Benign	0.044	D
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.72
MutPred		0.78		Gain of catalytic residue at N61 (P = 0.1479)
MVP		0.94
MPC		0.029
ClinPred		0.67	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.72
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		Position offset: 0

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

Other links and lift over

dbSNP: rs199475567; hg19: chr12-103306569;