rs199475637

chr12-102846895-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000277.3(PAH):c.969A>G(p.Thr323=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH NM_000277.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003335
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 O:1
• Conservation: PhyloP100: -0.331

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_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP7: Synonymous conserved (PhyloP=-0.331 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.969A>G	p.Thr323=	splice_region_variant, synonymous_variant	9/13	ENST00000553106.6
PAH	NM_001354304.2	c.969A>G	p.Thr323=	splice_region_variant, synonymous_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.969A>G	p.Thr323=	splice_region_variant, synonymous_variant	9/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251232 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460886 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 16, 2018	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Feb 13, 2021	The c.969A>G (p.Thr323=) variant in PAH has been found in a patient with PAH deficiency in cis with pathogenic variant IVS2–13T→G (PMID: 10394930). This variant has an extremely low frequency in gnomAD (MAF=0.00001). Splicing predictions are conflicting (HSF/MaxENT: probably no impact; TRAP 0.831: probably damaging). A functional study shows no significant effect on protein activity as compared to wild type (Relative PAH activity 114 +/-18, PMID: 18590700). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, BS3_supporting. -

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
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.2
Dann	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.080
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: rs199475637; hg19: chr12-103240673;