chr12-102852827-T-C

Position:

chr12-102852827-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3PP4PM5PM2PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.830A>G (p.Tyr277Cys) variant in PAH has been reported in multiple individuals with PKU (PMID:24350308). This variant has an extremely low allele frequency (MAF=0.00006) in gnomAD. It was detected with multiple pathogenic variants: p.R408W in 2 patients; p.L194P (PMID:24350308); c.842+1G>A in 2 patients (PMID:25952249). Computational prediction tools and conservation analysis support a deleterious effect. Another missense change at the same amino acid (p.Y277D), is pathogenic by 8 submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP3, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA229800/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

16

2

1

Clinical Significance

Pathogenic reviewed by expert panel P:3O:1

Conservation

PhyloP100: 6.24

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PM5

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.830A>G	p.Tyr277Cys	missense_variant	7/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.830A>G	p.Tyr277Cys	missense_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.830A>G	p.Tyr277Cys	missense_variant	7/13	1	NM_000277.3	ENSP00000448059.1		P00439
PAH	ENST00000307000.7 linkuse as main transcript	c.815A>G	p.Tyr272Cys	missense_variant	8/14	5		ENSP00000303500.2		J3KND8
PAH	ENST00000549247.6 linkuse as main transcript	n.589A>G		non_coding_transcript_exon_variant	1/6	2
PAH	ENST00000635477.1 linkuse as main transcript	c.-11A>G		upstream_gene_variant		5		ENSP00000489230.1		A0A0U1RQY4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152120

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

2

AN:

251346

Hom.:

0

AF XY:

0.00

AC XY:

0

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

4

AN:

1461760

Hom.:

0

Cov.:

31

AF XY:

0.00000275

AC XY:

2

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152120

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr277 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2035532, 8268925, 8632937, 12173030, 12655546). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102860). This missense change has been observed in individuals with phenylketonuria (PMID: 32668217). This variant is present in population databases (rs62516155, gnomAD 0.006%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 277 of the PAH protein (p.Tyr277Cys). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 16, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jun 08, 2020	The c.830A>G (p.Tyr277Cys) variant in PAH has been reported in multiple individuals with PKU (PMID:24350308). This variant has an extremely low allele frequency (MAF=0.00006) in gnomAD. It was detected with multiple pathogenic variants: p.R408W in 2 patients; p.L194P (PMID: 24350308); c.842+1G>A in 2 patients (PMID: 25952249). Computational prediction tools and conservation analysis support a deleterious effect. Another missense change at the same amino acid (p.Y277D), is pathogenic by 8 submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP3, PP4 -

not provided

Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

-

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.44

D

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

D

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.70

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.94

D

MutationAssessor

Pathogenic

4.8

H;.

PrimateAI

Pathogenic

0.86

D

PROVEAN

Pathogenic

-8.6

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.91

MutPred

0.93

Loss of phosphorylation at Y277 (P = 0.0319);.;

MVP

0.99

MPC

0.26

ClinPred

1.0

D

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Other links and lift over

dbSNP: rs62516155; hg19: chr12-103246605;