12-102839031-T-C

Position:

• chr12-102839031-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_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

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-102839031-T-C is Benign according to our data. Variant chr12-102839031-T-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 657680.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106	c.*144A>G		3_prime_UTR_variant	13/13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000	c.*144A>G		3_prime_UTR_variant	14/14	5		ENSP00000303500.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00223

Gnomad4 SAS exome AF: 0.00703

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000176

Gnomad4 OTH exome AF: 0.00133

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

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00250

Gnomad4 SAS AF: 0.00973

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 23, 2020	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 -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2023	- -

PAH-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2021

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs375319584; hg19: chr12-103232809;