rs79931499

Positions:

• chr12-102840477-C-A
• chr12-102840477-C-G
• chr12-102840477-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000277.3(PAH):​c.1238G>T​(p.Arg413Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R413H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.933

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a strand (size 6) in uniprot entity PH4H_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102840477-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.1238G>T	p.Arg413Leu	missense_variant	12/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1238G>T	p.Arg413Leu	missense_variant	13/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1238G>T	p.Arg413Leu	missense_variant	12/13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727154

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.013	B;.
Vest4		0.81
MutPred		0.85		Loss of methylation at R413 (P = 0.0508);.;
MVP		0.85
MPC		0.14
ClinPred		0.99	D
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-103234255;