NM_000277.3:c.464G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP1PP3PM3_StrongPM2PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.464G>A (p.Arg155His) has been reported in multiple individuals with mild hyperphenylalaninaemia, with BH4 deficiency excluded including 3 siblings (PP4_moderate, PMID:9634518; PP1, PMID:18937047). This variant has low frequency in ExAC/gnomad (MAF=0.00012) in EA population (PM2). Multiple lines of computational evidence support a deleterious effect (PP3). This variant has been detected with 3 pathogenic variants: R243Q (PMID:23932990), R111X (PMID:24401910), IVS4+5G>T c.441+5G>T (PMID:26210745) (PM3-strong). Experimental study showed the R155H mutant retained 55% activity, but this is higher than the cutoff set by PAH VCEP for PS3. (PMID:18937047). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong, PM2, PP3, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229559/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

14

4

Clinical Significance

Pathogenic reviewed by expert panel P:11O:1

Conservation

PhyloP100: 5.24

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

phenylketonuria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
classic phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
maternal phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild hyperphenylalaninemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PAH links:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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.

PP1

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.464G>A	p.Arg155His	missense	Exon 5 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.464G>A	p.Arg155His	missense	Exon 6 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.464G>A	p.Arg155His	missense	Exon 5 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.560G>A		non_coding_transcript_exon	Exon 5 of 6
	PAH	ENST00000906695.1		c.464G>A	p.Arg155His	missense	Exon 5 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

4

AN:

152132

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

5

AN:

251348

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

42

AN:

1461372

Hom.:

0

Cov.:

31

AF XY:

0.0000261

AC XY:

19

AN XY:

727016

show subpopulations

African (AFR)

AF:

0.0000598

AC:

2

AN:

33454

American (AMR)

AF:

0.0000671

AC:

3

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26124

East Asian (EAS)

AF:

0.0000756

AC:

3

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

1

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53414

Middle Eastern (MID)

AF:

0.000173

AC:

1

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000234

AC:

26

AN:

1111598

Other (OTH)

AF:

0.0000994

AC:

6

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0

3

6

8

11

14

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

2

4

6

8

10

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

4

AN:

152132

Hom.:

0

Cov.:

32

AF XY:

0.0000538

AC XY:

4

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41414

American (AMR)

AF:

0.00

AC:

0

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

1

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

1

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

2

AN:

68034

Other (OTH)

AF:

0.00

AC:

0

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0

1

1

2

2

3

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

0

2

4

6

8

10

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000298

Hom.:

0

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

3

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

10

-

-

Phenylketonuria (10)

1

-

-

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.44

D

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

29

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Uncertain

0.97

D

M_CAP

Pathogenic

0.81

D

MetaRNN

Pathogenic

0.97

D

MetaSVM

Pathogenic

0.96

D

MutationAssessor

Pathogenic

4.4

H

PhyloP100

5.2

PrimateAI

Uncertain

0.68

T

PROVEAN

Pathogenic

-4.7

D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D

Sift4G

Uncertain

0.0020

D

Polyphen

1.0

D

Vest4

0.85

MVP

0.99

MPC

0.26

ClinPred

1.0

D

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.91

Mutation Taster

=1/99

disease causing (ClinVar)

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

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Other links and lift over

dbSNP: rs199475663; hg19: chr12-103260419; COSMIC: COSV61016854; API