rs1801152

Variant names:

• chr12-102840473-G-A
• rs1801152
• NM_000277.3:c.1242C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102840473-G-A
• chr12-102840473-G-C
• chr12-102840473-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS2 BS1

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01361 in ENF from gnomAD; BS2: 19 homozygotes in gnomAD. 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: (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA200893/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.0076 (4 hom., cov: 32)
  • Exomes 𝑓: 0.012 (139 hom.)
• Consequence: PAH NM_000277.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:13 O:1
• Conservation: PhyloP100: 1.43
• Publications: 7 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 -8 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.1242C>T	p.Tyr414Tyr	synonymous	Exon 12 of 13	NP_000268.1
	PAH	NM_001354304.2		c.1242C>T	p.Tyr414Tyr	synonymous	Exon 13 of 14	NP_001341233.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.1242C>T	p.Tyr414Tyr	synonymous	Exon 12 of 13	ENSP00000448059.1
	PAH	ENST00000906695.1		c.1341C>T	p.Tyr447Tyr	synonymous	Exon 13 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.1320C>T	p.Tyr440Tyr	synonymous	Exon 12 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes AF: 0.00758 AC: 1153 AN: 152164 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00745 AC: 1874 AN: 251430 AF XY: 0.00730

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.0120 AC: 17485 AN: 1461530 Hom.: 139 Cov.: 31 AF XY: 0.0115 AC XY: 8369 AN XY: 727108

African (AFR) AF: 0.00200 AC: 67 AN: 33470

American (AMR) AF: 0.00376 AC: 168 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00179 AC: 154 AN: 86258

European-Finnish (FIN) AF: 0.00286 AC: 153 AN: 53412

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5766

European-Non Finnish (NFE) AF: 0.0148 AC: 16431 AN: 1111690

Other (OTH) AF: 0.00762 AC: 460 AN: 60390

GnomAD4 genome AF: 0.00757 AC: 1153 AN: 152282 Hom.: 4 Cov.: 32 AF XY: 0.00696 AC XY: 518 AN XY: 74452

African (AFR) AF: 0.00250 AC: 104 AN: 41552

American (AMR) AF: 0.00418 AC: 64 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0138 AC: 940 AN: 68034

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00963 Hom.: 9

Bravo AF: 0.00779

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0134

EpiControl AF: 0.0138

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (5)
-	-	4	Phenylketonuria (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.2
DANN	Benign	0.39
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1801152; hg19: chr12-103234251;