rs62516146

Positions:

chr12-102852810-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000277.3(PAH):c.842+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,878 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PAH
NM_000277.3 splice_region, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.91

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:

PAH (HGNC:):

PAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-102852810-C-T is Pathogenic according to our data. Variant chr12-102852810-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102852810-C-T is described in Lovd as [Pathogenic]. Variant chr12-102852810-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.842+5G>A		splice_region_variant, intron_variant		ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.842+5G>A		splice_region_variant, intron_variant			NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.842+5G>A	splice_region_variant, intron_variant	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000307000.7 linkuse as main transcript	c.827+5G>A	splice_region_variant, intron_variant	5		ENSP00000303500.2	J3KND8
PAH	ENST00000635477.1 linkuse as main transcript	c.2+5G>A	splice_region_variant, intron_variant	5		ENSP00000489230.1	A0A0U1RQY4
PAH	ENST00000549247.6 linkuse as main transcript	n.601+5G>A	splice_region_variant, intron_variant	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251264

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 24, 2020	Variant summary: PAH c.842+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site thereby predicting intron retention. At least one publication reports experimental evidence that this variant affects mRNA splicing by a similar mechanism (Liang_2014). The variant allele was found at a frequency of 4e-06 in 251264 control chromosomes. c.842+5G>A has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Guldberg_1996, Dobrowlski_2007, Langenbeck_2009, Zhu_2013, Liang_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an absence of normal activity in transfected COS-1 cells (Liang_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 19, 2024	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 23, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2023	This sequence change falls in intron 7 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs62516146, gnomAD 0.01%). This variant has been observed in individuals with phenylalanine hydroxylase deficiency (PMID: 8889590, 17502162, 19609714, 23932990, 24401910). This variant is also known as IVS7+5G>A. ClinVar contains an entry for this variant (Variation ID: 102872). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24401910). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2014	The 842+5G>A variant in PAH has been reported in 1 German individual with PKU who was compound heterozygous for the pathogenic Arg408Trp variant (Guldberg 1996). This variant has also been identified in 1/8600 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs62516146). This variant is located in the 5' splice region and is predicted to cause altered splicing leading to an abnormal or absent protein. Of note, several other variants at this splice region have been reported in individuals with PKU. In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. -

not provided

Pathogenic:4Other:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2021	Non-canonical splice site variant demonstrated to result in loss-of-function (Liang et al., 2014); Expression studies found that this variant is associated with less than 1% residual enzyme activity compared to wild-type (Liang et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24401910, 17935162, 27535533, 32668217, 29499199, 25466353, 8889590, 25525159) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 29, 2024	PP3, PM2_moderate, PM3_very_strong -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.93

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.93

Position offset: 5

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over