chr12-102904739-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000277.3(PAH):​c.168+8052T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 505,486 control chromosomes in the GnomAD database, including 40,214 homozygotes. 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: 𝑓 0.44 (16751 hom., cov: 31)
  • Exomes 𝑓: 0.35 (23463 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.39

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.168+8052T>C		intron_variant	Intron 2 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.168+8052T>C		intron_variant	Intron 3 of 13		NP_001341233.1
PAH	XM_017019370.2	c.168+8052T>C		intron_variant	Intron 2 of 6		XP_016874859.1
LOC124902999	XR_007063428.1	n.904A>G		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.168+8052T>C		intron_variant	Intron 2 of 12	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66565 AN: 151854 Hom.: 16710 Cov.: 31

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.419

GnomAD3 exomes AF: 0.369 AC: 81491 AN: 221084 Hom.: 16916 AF XY: 0.355 AC XY: 43492 AN XY: 122420

Gnomad AFR exome AF: 0.693

Gnomad AMR exome AF: 0.542

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.218

Gnomad SAS exome AF: 0.320

Gnomad FIN exome AF: 0.227

Gnomad NFE exome AF: 0.329

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.348 AC: 122999 AN: 353514 Hom.: 23463 Cov.: 0 AF XY: 0.341 AC XY: 69391 AN XY: 203432

Gnomad4 AFR exome AF: 0.681

Gnomad4 AMR exome AF: 0.541

Gnomad4 ASJ exome AF: 0.349

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.327

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.323

Gnomad4 OTH exome AF: 0.340

GnomAD4 genome AF: 0.439 AC: 66646 AN: 151972 Hom.: 16751 Cov.: 31 AF XY: 0.433 AC XY: 32160 AN XY: 74274

Gnomad4 AFR AF: 0.686

Gnomad4 AMR AF: 0.510

Gnomad4 ASJ AF: 0.383

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.415

Alfa AF: 0.345 Hom.: 18452

Bravo AF: 0.472

Asia WGS AF: 0.310 AC: 1078 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.65
DANN	Benign	0.30

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: rs1522307; hg19: chr12-103298517; COSMIC: COSV61019171;