rs1851381

Positions:

• chr12-102904593-T-A

Variant summary

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

The ENST00000553106.6(PAH):​c.168+8198A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0536 in 237,348 control chromosomes in the GnomAD database, including 425 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 0.059 (303 hom., cov: 32)
  • Exomes 𝑓: 0.045 (122 hom.)
• Consequence: PAH ENST00000553106.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.529

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.168+8198A>T		intron_variant		ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1	n.863-105T>A		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.168+8198A>T		intron_variant			NP_001341233.1
PAH	XM_017019370.2	c.168+8198A>T		intron_variant			XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.168+8198A>T		intron_variant		1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes AF: 0.0587 AC: 8933 AN: 152198 Hom.: 304 Cov.: 32

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0848

Gnomad EAS AF: 0.00827

Gnomad SAS AF: 0.0809

Gnomad FIN AF: 0.0446

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0679

Gnomad OTH AF: 0.0612

GnomAD4 exome AF: 0.0446 AC: 3792 AN: 85032 Hom.: 122 AF XY: 0.0447 AC XY: 2150 AN XY: 48120

Gnomad4 AFR exome AF: 0.0230

Gnomad4 AMR exome AF: 0.0847

Gnomad4 ASJ exome AF: 0.0563

Gnomad4 EAS exome AF: 0.00297

Gnomad4 SAS exome AF: 0.0504

Gnomad4 FIN exome AF: 0.0373

Gnomad4 NFE exome AF: 0.0460

Gnomad4 OTH exome AF: 0.0446

GnomAD4 genome AF: 0.0586 AC: 8924 AN: 152316 Hom.: 303 Cov.: 32 AF XY: 0.0583 AC XY: 4344 AN XY: 74490

Gnomad4 AFR AF: 0.0306

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0848

Gnomad4 EAS AF: 0.00829

Gnomad4 SAS AF: 0.0807

Gnomad4 FIN AF: 0.0446

Gnomad4 NFE AF: 0.0679

Gnomad4 OTH AF: 0.0605

Alfa AF: 0.0612 Hom.: 36

Bravo AF: 0.0590

Asia WGS AF: 0.0670 AC: 233 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
DANN	Benign	0.51

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: rs1851381; hg19: chr12-103298371;