12-102912791-C-T

Variant names:

• chr12-102912791-C-T
• rs199475567
• NM_000277.3:c.168G>A

Variant summary

Our verdict is Uncertain significance. The variant received -2 ACMG points: 3P and 5B. BS2 PP3 BP2 PM2

This summary comes from the ClinGen Evidence Repository: The c.168G>A (p.Glu56=) variant in PAH has been reported as a polymoprhism. It was found in Arab patients’ DNA, including patients and controls (zygosity not reported). (BS2; PMID:18299955) However, this variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). While it is a synonymous variant, alteration of the WT donor site affecting splicing is suggested by Human Splicing Finder and Alamut (PP3). It was observed in cis with a pathogenic variant, IVS2+1G>A (BP2; PMID:24368688). In summary, this variant meets criteria to be classified as uncertain significance for PAH due to conflicting evidence. ACMG/AMP criteria applied: BS2, BP2, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229457/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAH NM_000277.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance reviewed by expert panel U:3 B:1 O:1
• Conservation: PhyloP100: 2.59
• Publications: 8 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 -2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.168G>A	p.Glu56Glu	splice_region synonymous	Exon 2 of 13	NP_000268.1
	PAH	NM_001354304.2		c.168G>A	p.Glu56Glu	splice_region synonymous	Exon 3 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.168G>A	p.Glu56Glu	splice_region synonymous	Exon 2 of 13	ENSP00000448059.1
	PAH	ENST00000549111.5	TSL:1	n.264G>A		splice_region non_coding_transcript_exon	Exon 2 of 6
	PAH	ENST00000906695.1		c.168G>A	p.Glu56Glu	splice_region synonymous	Exon 2 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449126 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 721946

African (AFR) AF: 0.00 AC: 0 AN: 33222

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 85994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100470

Other (OTH) AF: 0.00 AC: 0 AN: 59994

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Phenylketonuria (2)
-	1	-	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.76
PhyloP100		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199475567; hg19: chr12-103306569;