chr12-102839156-C-A

Variant names:

• chr12-102839156-C-A
• rs372637021
• NM_000277.3:c.*19G>T

Variant summary

Our verdict is Uncertain significance. The variant received -3 ACMG points: 1P and 4B. PP4 BS1

This summary comes from the ClinGen Evidence Repository: The c.*19G>T variant in PAH has been reported in a 2 patients with PKU (PP4; PMID:12765842, 26210745) This variant has an allele frequency greater than expected: gnomAD MAF=0.00812 (>0.002) and 8 homozygotes (BS1). Computational evidence is conflicting (TraP score: 0.085; HSF: activation of an exonic cryptic donor site; MaxENT 3' Motif:+1145.71). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748669/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (14 hom.)
• Consequence: PAH NM_000277.3 3_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:3 B:5
• Conservation: PhyloP100: -0.654
• 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: Uncertain_significance. The variant received -3 ACMG points.

• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.*19G>T		3_prime_UTR	Exon 13 of 13	NP_000268.1
	PAH	NM_001354304.2		c.*19G>T		3_prime_UTR	Exon 14 of 14	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.*19G>T		3_prime_UTR	Exon 13 of 13	ENSP00000448059.1
	PAH	ENST00000906695.1		c.*19G>T		3_prime_UTR	Exon 14 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.*19G>T		3_prime_UTR	Exon 13 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 194 AN: 152212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00219 AC: 550 AN: 250934 AF XY: 0.00271

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00250

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00129 AC: 1882 AN: 1455368 Hom.: 14 Cov.: 29 AF XY: 0.00157 AC XY: 1140 AN XY: 724392

African (AFR) AF: 0.0000300 AC: 1 AN: 33356

American (AMR) AF: 0.00177 AC: 79 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000728 AC: 19 AN: 26100

East Asian (EAS) AF: 0.00131 AC: 52 AN: 39666

South Asian (SAS) AF: 0.00822 AC: 708 AN: 86100

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53306

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5762

European-Non Finnish (NFE) AF: 0.000777 AC: 859 AN: 1106234

Other (OTH) AF: 0.00153 AC: 92 AN: 60154

GnomAD4 genome AF: 0.00127 AC: 194 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74488

African (AFR) AF: 0.000240 AC: 10 AN: 41582

American (AMR) AF: 0.00340 AC: 52 AN: 15302

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

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5188

South Asian (SAS) AF: 0.00786 AC: 38 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.00114

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	3	1	Phenylketonuria (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs372637021; hg19: chr12-103232934; COSMIC: COSV107395860; COSMIC: COSV107395860;