rs1522296

Variant names:

• chr12-102917009-G-A
• rs1522296
• NM_000277.3:c.60+62C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102917009-G-A
• chr12-102917009-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP7

This summary comes from the ClinGen Evidence Repository: The c.60+62C>T intronic variant in PAH has a MAF of 0.3441 in gnomAD with 2,014 homozygotes.In summary, this variant meets criteria to be classified as benign for PAH. PAH-specific ACMG/AMP criteria applied: BA1, BS2, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA13630270/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.37 (11390 hom., cov: 33)
  • Exomes 𝑓: 0.32 (69576 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Benign reviewed by expert panel P:1 B:11
• Conservation: PhyloP100: -0.508
• Publications: 15 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

Our verdict: Benign. The variant received -9 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• 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.60+62C>T		intron	N/A	NP_000268.1	P00439
	PAH	NM_001354304.2		c.60+62C>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.60+62C>T		intron	N/A	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.156+62C>T		intron	N/A
	PAH	ENST00000906695.1		c.60+62C>T		intron	N/A	ENSP00000576754.1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56513 AN: 151900 Hom.: 11360 Cov.: 33

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.371

GnomAD4 exome AF: 0.320 AC: 416270 AN: 1299882 Hom.: 69576 AF XY: 0.318 AC XY: 208511 AN XY: 655128

African (AFR) AF: 0.506 AC: 15332 AN: 30282

American (AMR) AF: 0.525 AC: 23360 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 8878 AN: 25122

East Asian (EAS) AF: 0.224 AC: 8710 AN: 38930

South Asian (SAS) AF: 0.305 AC: 25314 AN: 82910

European-Finnish (FIN) AF: 0.199 AC: 10604 AN: 53188

Middle Eastern (MID) AF: 0.297 AC: 1630 AN: 5484

European-Non Finnish (NFE) AF: 0.316 AC: 304479 AN: 964366

Other (OTH) AF: 0.326 AC: 17963 AN: 55098

GnomAD4 genome AF: 0.372 AC: 56582 AN: 152018 Hom.: 11390 Cov.: 33 AF XY: 0.369 AC XY: 27407 AN XY: 74308

African (AFR) AF: 0.502 AC: 20796 AN: 41420

American (AMR) AF: 0.477 AC: 7286 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1287 AN: 3470

East Asian (EAS) AF: 0.221 AC: 1138 AN: 5158

South Asian (SAS) AF: 0.316 AC: 1521 AN: 4820

European-Finnish (FIN) AF: 0.192 AC: 2027 AN: 10584

Middle Eastern (MID) AF: 0.277 AC: 81 AN: 292

European-Non Finnish (NFE) AF: 0.315 AC: 21385 AN: 67962

Other (OTH) AF: 0.367 AC: 775 AN: 2112

Alfa AF: 0.244 Hom.: 787

Bravo AF: 0.400

Asia WGS AF: 0.296 AC: 1031 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	5	Phenylketonuria (6)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	PAH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.98
DANN	Benign	0.43
PhyloP100		-0.51
PromoterAI		-0.0090	Neutral
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: rs1522296; hg19: chr12-103310787; COSMIC: COSV61015018; COSMIC: COSV61015018;