12-102839031-T-C

Variant names:

• chr12-102839031-T-C
• rs375319584
• NM_000277.3:c.*144A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000277.3(PAH):​c.*144A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000828 in 723,064 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (8 hom.)
• Consequence: PAH NM_000277.3 3_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: 0.267
• Publications: 0 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.*144A>G		3_prime_UTR_variant	Exon 13 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.*144A>G		3_prime_UTR_variant	Exon 14 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.*144A>G		3_prime_UTR_variant	Exon 13 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000941 AC: 537 AN: 570696 Hom.: 8 Cov.: 7 AF XY: 0.00118 AC XY: 362 AN XY: 306426

African (AFR) AF: 0.00 AC: 0 AN: 15324

American (AMR) AF: 0.00 AC: 0 AN: 31932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18824

East Asian (EAS) AF: 0.00223 AC: 72 AN: 32308

South Asian (SAS) AF: 0.00703 AC: 416 AN: 59174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37316

Middle Eastern (MID) AF: 0.000509 AC: 2 AN: 3926

European-Non Finnish (NFE) AF: 0.0000176 AC: 6 AN: 341038

Other (OTH) AF: 0.00133 AC: 41 AN: 30854

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000617 AC XY: 46 AN XY: 74514

African (AFR) AF: 0.0000481 AC: 2 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00250 AC: 13 AN: 5192

South Asian (SAS) AF: 0.00973 AC: 47 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000132

Asia WGS AF: 0.0200 AC: 69 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:1 Benign:2

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000277.3(PAH):c.*144A>G (ClinVar variant ID 657680) is a 3’ UTR variant in PAH. The variant has been previously reported as a single heterozygous variant in a proband with classic PKU (PMID: 20188615), with plasma Phe 1105 umol/L; BH4 deficiency does not appear to have been formally excluded (PP4). The authors speculated that the variant could “either affect the half life of the mRNA or its translation efficiency,” but did not perform functional validation studies. The variant was absent in the mother, who was unaffected, and present as a single heterozygous variant in the father, who was also unaffected. The authors were unable to detect a second variant in the (affected) proband, which they argued could be due to it being “located in PAH intronic regions not covered in the screening strategy.” It has also been found as a single heterozygous variant in a screening study of 3,552 healthy Japanese adults (PMID: 30887117). In ClinVar (ClinVar variant ID 657680), it is classified as VUS by one lab and Likely Benign by one lab, based on the above literature reports and uncertain functional consequences. Four heterozygotes and zero homozygotes are present for the variant in gnomAD; corresponding to a global AF of 0.000127 and maximum population frequency of 0.00128 (East Asian population), less than the 0.002 frequency threshold for use of BS1 and greater than the 0.0002 frequency threshold for use of PM2. The variant is predicted to not significantly alter splicing by multiple predictors (Splice AI score 0.00, MaxEntScan score variation 0.00%) (BP4). Classification: VUS Supporting Criteria: PP4; BP4 -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

PAH-related disorder Benign:1

Mar 08, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.1
DANN	Benign	0.55
PhyloP100		0.27
Mutation Taster		=11/89	disease causing

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: rs375319584; hg19: chr12-103232809;