Genetic Variant NM_000277.3:c.913-459T>C (chr12-102847410-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

3 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), G2P, ClinGen, Myriad Women’s Health
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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

African (AFR)

AF:

0.207

AC:

320

AN:

1546

American (AMR)

AF:

0.261

AC:

941

AN:

3602

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

203

AN:

768

East Asian (EAS)

AF:

0.0448

AC:

140

AN:

3128

South Asian (SAS)

AF:

0.301

AC:

976

AN:

3244

European-Finnish (FIN)

AF:

0.350

AC:

286

AN:

816

Middle Eastern (MID)

AF:

0.207

AC:

AN:

116

European-Non Finnish (NFE)

AF:

0.364

AC:

6998

AN:

19226

Other (OTH)

AF:

0.337

AC:

562

AN:

1668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

314

627

941

1254

1568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.319

AC:

48444

AN:

152072

Hom.:

8223

Cov.:

AF XY:

0.321

AC XY:

23831

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.234

AC:

9716

AN:

41506

American (AMR)

AF:

0.275

AC:

4203

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

973

AN:

3470

East Asian (EAS)

AF:

0.0533

AC:

276

AN:

5182

South Asian (SAS)

AF:

0.300

AC:

1445

AN:

4816

European-Finnish (FIN)

AF:

0.427

AC:

4500

AN:

10548

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.385

AC:

26137

AN:

67956

Other (OTH)

AF:

0.328

AC:

693

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1664

3328

4993

6657

8321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

488

976

1464

1952

2440

<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:

0.350

Hom.:

39388

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

(source)

DANN

Benign

0.32

PhyloP100

-0.94

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over