Variant chr12-102866681-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP7

This summary comes from the ClinGen Evidence Repository: The c.442-18G>A variant in PAH has not been reported in the literature to our knowledge. This variant has a MAF of 0.00067 in the gnomAD Latino population. This is too high for PM2, but too low for BS1 per PAH EP guidelines. No splicing impact is predicted in HSF or MaxEnt (BP7). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748923/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

PAH
NM_000277.3 intron

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:2

Conservation

PhyloP100: -0.193

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:

LOC124902999 (HGNC:):

LOC124902999 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

BP7

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
PAH	NM_000277.3 linkuse as main transcript	c.442-18G>A	intron_variant	ENST00000553106.6
LOC124902999	XR_007063428.1 linkuse as main transcript	n.807+1454C>T	intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2 linkuse as main transcript	c.442-18G>A	intron_variant
PAH	XM_017019370.2 linkuse as main transcript	c.442-18G>A	intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
PAH	ENST00000553106.6 linkuse as main transcript	c.442-18G>A	intron_variant	1	NM_000277.3	P1
PAH	ENST00000549111.5 linkuse as main transcript	n.538-18G>A	intron_variant, non_coding_transcript_variant	1
PAH	ENST00000307000.7 linkuse as main transcript	c.427-18G>A	intron_variant	5
PAH	ENST00000551988.5 linkuse as main transcript	n.530+10781G>A	intron_variant, non_coding_transcript_variant	3

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000179

AC:

AN:

251142

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000695

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000129

AC:

188

AN:

1455350

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

724452

show subpopulations

Gnomad4 AFR exome

AF:

0.000660

Gnomad4 AMR exome

AF:

0.000515

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000886

Gnomad4 OTH exome

AF:

0.000233

GnomAD4 genome

AF:

0.000151

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Sep 27, 2019	The c.442-18G>A variant in PAH has not been reported in the literature to our knowledge. This variant has a MAF of 0.00067 in the gnomAD Latino population. This is too high for PM2, but too low for BS1 per PAH EP guidelines. No splicing impact is predicted in HSF or MaxEnt (BP7). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: BP7. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

4.9

DANN

Benign

0.66

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over