Genetic Variant NM_000277.3:c.707-925T>A (chr12-102853875-A-T) – 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.707-925T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,090 control chromosomes in the GnomAD database, including 4,792 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 0.23 ( 4792 hom., cov: 32)

Consequence

PAH
NM_000277.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.385

Publications

1 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=-0.88).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.707-925T>A	intron_variant	Intron 6 of 12	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	XM_017019370.2 link	c.*910T>A	3_prime_UTR_variant	Exon 7 of 7		XP_016874859.1
PAH	NM_001354304.2 link	c.707-925T>A	intron_variant	Intron 7 of 13		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.707-925T>A		intron_variant	Intron 6 of 12	1	NM_000277.3	ENSP00000448059.1		P00439
PAH	ENST00000307000.7 link	c.692-925T>A		intron_variant	Intron 7 of 13	5		ENSP00000303500.2		J3KND8

Frequencies

GnomAD3 genomes

AF:

0.228

AC:

34618

AN:

151972

Hom.:

4778

Cov.:

show subpopulations

Gnomad AFR

AF:

0.343

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.363

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.0320

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.0992

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.219

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.228

AC:

34655

AN:

152090

Hom.:

4792

Cov.:

AF XY:

0.226

AC XY:

16803

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.343

AC:

14205

AN:

41430

American (AMR)

AF:

0.363

AC:

5553

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

694

AN:

3470

East Asian (EAS)

AF:

0.0316

AC:

164

AN:

5182

South Asian (SAS)

AF:

0.166

AC:

799

AN:

4814

European-Finnish (FIN)

AF:

0.0992

AC:

1052

AN:

10606

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.171

AC:

11598

AN:

67992

Other (OTH)

AF:

0.217

AC:

458

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1278

2557

3835

5114

6392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

340

680

1020

1360

1700

<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:

0.203

Hom.:

454

Bravo

AF:

0.251

Asia WGS

AF:

0.115

AC:

402

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

9.3

(source)

DANN

Benign

0.81

PhyloP100

0.39

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over