rs1522306

Variant names:

• chr12-102846852-C-A
• rs1522306
• NM_000277.3:c.969+43G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.49022 in ExAC. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA145984/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.36 (10523 hom., cov: 32)
  • Exomes 𝑓: 0.40 (116538 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Benign reviewed by expert panel B:6 O:1
• Conservation: PhyloP100: -1.11
• Publications: 6 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), 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

ACMG classification

Specifications for PAH are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: 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.969+43G>T		intron	N/A	NP_000268.1	P00439
	PAH	NM_001354304.2		c.969+43G>T		intron	N/A	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.969+43G>T		intron	N/A	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1068+43G>T		intron	N/A	ENSP00000576754.1
	PAH	ENST00000906692.1		c.969+43G>T		intron	N/A	ENSP00000576751.1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54663 AN: 151902 Hom.: 10514 Cov.: 32

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.366

GnomAD2 exomes AF: 0.351 AC: 88020 AN: 250424 AF XY: 0.359

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.0555

Gnomad FIN exome AF: 0.490

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.403 AC: 555142 AN: 1377846 Hom.: 116538 Cov.: 22 AF XY: 0.402 AC XY: 277660 AN XY: 690566

African (AFR) AF: 0.269 AC: 8501 AN: 31618

American (AMR) AF: 0.255 AC: 11357 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8445 AN: 25618

East Asian (EAS) AF: 0.0463 AC: 1818 AN: 39276

South Asian (SAS) AF: 0.349 AC: 29491 AN: 84598

European-Finnish (FIN) AF: 0.487 AC: 25978 AN: 53338

Middle Eastern (MID) AF: 0.392 AC: 2186 AN: 5580

European-Non Finnish (NFE) AF: 0.430 AC: 445235 AN: 1035596

Other (OTH) AF: 0.384 AC: 22131 AN: 57654

GnomAD4 genome AF: 0.360 AC: 54701 AN: 152020 Hom.: 10523 Cov.: 32 AF XY: 0.363 AC XY: 26937 AN XY: 74280

African (AFR) AF: 0.273 AC: 11332 AN: 41450

American (AMR) AF: 0.312 AC: 4774 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1106 AN: 3472

East Asian (EAS) AF: 0.0552 AC: 286 AN: 5184

South Asian (SAS) AF: 0.334 AC: 1603 AN: 4806

European-Finnish (FIN) AF: 0.508 AC: 5354 AN: 10544

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28969 AN: 67962

Other (OTH) AF: 0.368 AC: 777 AN: 2110

Alfa AF: 0.395 Hom.: 3998

Bravo AF: 0.340

Asia WGS AF: 0.233 AC: 810 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	2	not specified (2)
-	-	2	Phenylketonuria (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.28
DANN	Benign	0.77
PhyloP100		-1.1
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: rs1522306; hg19: chr12-103240630; COSMIC: COSV61015928;