Genetic Variant PAH:c.913-459T>C (chr12-102847410-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000277.3(PAH):c.913-459T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 186,186 control chromosomes in the GnomAD database, including 10,089 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.32 ( 8223 hom., cov: 32)

Exomes 𝑓: 0.31 ( 1866 hom. )

Consequence

PAH
NM_000277.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.935

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.913-459T>C		intron_variant	Intron 8 of 12	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.913-459T>C		intron_variant	Intron 9 of 13		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.913-459T>C		intron_variant	Intron 8 of 12	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.319

AC:

48423

AN:

151954

Hom.:

8218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.234

Gnomad AMI

AF:

0.437

Gnomad AMR

AF:

0.275

Gnomad ASJ

AF:

0.280

Gnomad EAS

AF:

0.0531

Gnomad SAS

AF:

0.298

Gnomad FIN

AF:

0.427

Gnomad MID

AF:

0.364

Gnomad NFE

AF:

0.385

Gnomad OTH

AF:

0.326

GnomAD4 exome

AF:

0.306

AC:

10450

AN:

34114

Hom.:

1866

Cov.:

AF XY:

0.303

AC XY:

5312

AN XY:

17546

show subpopulations

Gnomad4 AFR exome

AF:

0.207

Gnomad4 AMR exome

AF:

0.261

Gnomad4 ASJ exome

AF:

0.264

Gnomad4 EAS exome

AF:

0.0448

Gnomad4 SAS exome

AF:

0.301

Gnomad4 FIN exome

AF:

0.350

Gnomad4 NFE exome

AF:

0.364

Gnomad4 OTH exome

AF:

0.337

GnomAD4 genome

AF:

0.319

AC:

48444

AN:

152072

Hom.:

8223

Cov.:

AF XY:

0.321

AC XY:

23831

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.234

Gnomad4 AMR

AF:

0.275

Gnomad4 ASJ

AF:

0.280

Gnomad4 EAS

AF:

0.0533

Gnomad4 SAS

AF:

0.300

Gnomad4 FIN

AF:

0.427

Gnomad4 NFE

AF:

0.385

Gnomad4 OTH

AF:

0.328

Alfa

AF:

0.355

Hom.:

16844

Bravo

AF:

0.303

Asia WGS

AF:

0.217

AC:

756

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.62

DANN

Benign

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over