rs398123291

chr12-102894768-GGACAGTGGC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM4 PP3 PP5_Strong

The NM_000277.3(PAH):c.310_318del(p.Ala104_Val106del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. A104A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 8.30

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]

LOC124902999 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000277.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000277.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 12-102894768-GGACAGTGGC-G is Pathogenic according to our data. Variant chr12-102894768-GGACAGTGGC-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 92740.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.310_318del	p.Ala104_Val106del	inframe_deletion	3/13	ENST00000553106.6
LOC124902999	XR_007063428.1	n.863-9929_863-9921del		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.310_318del	p.Ala104_Val106del	inframe_deletion	4/14
PAH	XM_017019370.2	c.310_318del	p.Ala104_Val106del	inframe_deletion	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.310_318del	p.Ala104_Val106del	inframe_deletion	3/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251448 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135888

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 10, 2018	PAH-specific ACMG/AMP criteria applied: PM2: Identified a single time in gnomAD (4.06e-06) and absent in ExAC; PM4: p.Ala104_Val106del; PP4: Single patient picked up on NBS with no confirmation studies, no clinical info, no Phe levels, etc. (PMID:27308838). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM4, PP4). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 15, 2023	This variant, c.310_318del, results in the deletion of 3 amino acid(s) of the PAH protein (p.Ala104_Val106del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs398123291, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 92740). This variant disrupts a region of the PAH protein in which other variant(s) (p.Ala104Asp) have been determined to be pathogenic (PMID: 18299955, 22112818, 22526846, 23764561, 26666653). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 29, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398123291; hg19: chr12-103288546;