rs1722387

Variant names:

• chr12-102847292-T-C
• rs1722387
• NM_000277.3:c.913-341A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000277.3(PAH):​c.913-341A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 358,714 control chromosomes in the GnomAD database, including 133,868 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 0.86 (55983 hom., cov: 32)
  • Exomes 𝑓: 0.87 (77885 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.710
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.913-341A>G		intron_variant	Intron 8 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.913-341A>G		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	c.913-341A>G		intron_variant	Intron 8 of 12	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.857 AC: 130354 AN: 152086 Hom.: 55942 Cov.: 32

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.794

Gnomad AMR AF: 0.890

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.850

Gnomad SAS AF: 0.916

Gnomad FIN AF: 0.907

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.849

Gnomad OTH AF: 0.857

GnomAD4 exome AF: 0.868 AC: 179163 AN: 206510 Hom.: 77885 Cov.: 0 AF XY: 0.873 AC XY: 96110 AN XY: 110118

African (AFR) AF: 0.845 AC: 5417 AN: 6414

American (AMR) AF: 0.898 AC: 9946 AN: 11072

Ashkenazi Jewish (ASJ) AF: 0.836 AC: 4614 AN: 5516

East Asian (EAS) AF: 0.851 AC: 8974 AN: 10540

South Asian (SAS) AF: 0.924 AC: 30276 AN: 32764

European-Finnish (FIN) AF: 0.908 AC: 8667 AN: 9546

Middle Eastern (MID) AF: 0.838 AC: 657 AN: 784

European-Non Finnish (NFE) AF: 0.851 AC: 101132 AN: 118882

Other (OTH) AF: 0.862 AC: 9480 AN: 10992

GnomAD4 genome AF: 0.857 AC: 130452 AN: 152204 Hom.: 55983 Cov.: 32 AF XY: 0.862 AC XY: 64133 AN XY: 74416

African (AFR) AF: 0.845 AC: 35082 AN: 41536

American (AMR) AF: 0.890 AC: 13599 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 2869 AN: 3472

East Asian (EAS) AF: 0.850 AC: 4389 AN: 5166

South Asian (SAS) AF: 0.915 AC: 4418 AN: 4828

European-Finnish (FIN) AF: 0.907 AC: 9608 AN: 10596

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.849 AC: 57709 AN: 68012

Other (OTH) AF: 0.858 AC: 1810 AN: 2110

Alfa AF: 0.847 Hom.: 69361

Bravo AF: 0.852

Asia WGS AF: 0.867 AC: 3019 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.0
DANN	Benign	0.78
PhyloP100		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1722387; hg19: chr12-103241070;