rs1555204295

Variant names:

• chr12-102851689-G-A
• rs1555204295
• NM_000277.3:c.910C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102851689-G-A
• chr12-102851689-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4 PM2_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The c.910C>T (p.Gln304Ter) variant in PAH has been reported in at least 1 individual with PKU however without indication of the genotype (BH4 deficiency not ruled out) (PMID:23357515) . This variant occurs in exon 8 of 13 of PAH, a gene where loss of function is a known disease mechanism, and is predicted to result in a truncated protein (with truncation of >10% of the encoded protein) or mRNA subject to nonsense-mediated decay. The c.910C>T variant is absent from gnomAD and the ESP population databases. Based on available information, this variant is considered to be pathogenic. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020892/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.60
• Publications: 0 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), ClinGen, Myriad Women’s Health, G2P
• 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 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.910C>T	p.Gln304*	stop_gained splice_region	Exon 8 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.910C>T	p.Gln304*	stop_gained splice_region	Exon 9 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.910C>T	p.Gln304*	stop_gained splice_region	Exon 8 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1009C>T	p.Gln337*	stop_gained splice_region	Exon 9 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.910C>T	p.Gln304*	stop_gained splice_region	Exon 8 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Phenylketonuria (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	51
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.6
Vest4		0.98
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.13		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: rs1555204295; hg19: chr12-103245467;