rs1851381

Variant names:

• chr12-102904593-T-A
• rs1851381
• NM_000277.3:c.168+8198A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000277.3(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 NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.529
• Publications: 2 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

LOC124902999 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.168+8198A>T		intron_variant	Intron 2 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.168+8198A>T		intron_variant	Intron 3 of 13		NP_001341233.1
PAH	XM_017019370.2	c.168+8198A>T		intron_variant	Intron 2 of 6		XP_016874859.1
LOC124902999	XR_007063428.1	n.863-105T>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.168+8198A>T		intron_variant	Intron 2 of 12	1	NM_000277.3	ENSP00000448059.1

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

African (AFR) AF: 0.0230 AC: 51 AN: 2220

American (AMR) AF: 0.0847 AC: 353 AN: 4170

Ashkenazi Jewish (ASJ) AF: 0.0563 AC: 98 AN: 1740

East Asian (EAS) AF: 0.00297 AC: 16 AN: 5390

South Asian (SAS) AF: 0.0504 AC: 816 AN: 16204

European-Finnish (FIN) AF: 0.0373 AC: 185 AN: 4964

Middle Eastern (MID) AF: 0.0231 AC: 40 AN: 1730

European-Non Finnish (NFE) AF: 0.0460 AC: 2065 AN: 44850

Other (OTH) AF: 0.0446 AC: 168 AN: 3764

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

African (AFR) AF: 0.0306 AC: 1274 AN: 41584

American (AMR) AF: 0.109 AC: 1665 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 294 AN: 3468

East Asian (EAS) AF: 0.00829 AC: 43 AN: 5190

South Asian (SAS) AF: 0.0807 AC: 389 AN: 4818

European-Finnish (FIN) AF: 0.0446 AC: 473 AN: 10608

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0679 AC: 4618 AN: 68034

Other (OTH) AF: 0.0605 AC: 128 AN: 2114

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
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

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: rs1851381; hg19: chr12-103298371;