rs1522307

Variant names:

• chr12-102904739-A-C
• rs1522307
• NM_000277.3:c.168+8052T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-102904739-A-C
• chr12-102904739-A-G
• chr12-102904739-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000277.3(PAH):​c.168+8052T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 356,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.39
• Publications: 20 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), ClinGen, Myriad Women’s Health, G2P
• 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

LOC124902999 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.168+8052T>G		intron	N/A	NP_000268.1	P00439
	PAH	NM_001354304.2		c.168+8052T>G		intron	N/A	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.168+8052T>G		intron	N/A	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.264+8052T>G		intron	N/A
	PAH	ENST00000906695.1		c.168+8052T>G		intron	N/A	ENSP00000576754.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000452 AC: 1 AN: 221084 AF XY: 0.00000817

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000561 AC: 2 AN: 356384 Hom.: 0 Cov.: 0 AF XY: 0.00000488 AC XY: 1 AN XY: 205040

African (AFR) AF: 0.00 AC: 0 AN: 9818

American (AMR) AF: 0.0000594 AC: 2 AN: 33676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11330

East Asian (EAS) AF: 0.00 AC: 0 AN: 13066

South Asian (SAS) AF: 0.00 AC: 0 AN: 64748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2798

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 188048

Other (OTH) AF: 0.00 AC: 0 AN: 16194

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 35149

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.58
DANN	Benign	0.39
PhyloP100		-2.4

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: rs1522307; hg19: chr12-103298517;