12-102918841-C-A

Variant names:

• chr12-102918841-C-A
• rs7485331
• NM_001354304.2:c.-95-1616G>T

Variant summary

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

The NM_001354304.2(PAH):​c.-95-1616G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 151,924 control chromosomes in the GnomAD database, including 13,687 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 0.40 (13687 hom., cov: 32)
• Consequence: PAH NM_001354304.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.548
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_001354304.2	c.-95-1616G>T		intron_variant	Intron 1 of 13		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000551337.5	c.-95-1616G>T		intron_variant	Intron 1 of 4	3		ENSP00000447620.1
PAH	ENST00000546844.1	c.-95-1616G>T		intron_variant	Intron 1 of 3	3		ENSP00000446658.1
PAH	ENST00000546708.5	n.493-1616G>T		intron_variant	Intron 4 of 4	5

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61032 AN: 151806 Hom.: 13644 Cov.: 32

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.385

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

GnomAD4 genome AF: 0.402 AC: 61116 AN: 151924 Hom.: 13687 Cov.: 32 AF XY: 0.398 AC XY: 29581 AN XY: 74250

African (AFR) AF: 0.590 AC: 24428 AN: 41414

American (AMR) AF: 0.488 AC: 7449 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1289 AN: 3466

East Asian (EAS) AF: 0.239 AC: 1239 AN: 5178

South Asian (SAS) AF: 0.321 AC: 1542 AN: 4804

European-Finnish (FIN) AF: 0.196 AC: 2071 AN: 10542

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21922 AN: 67944

Other (OTH) AF: 0.381 AC: 804 AN: 2110

Alfa AF: 0.357 Hom.: 3651

Bravo AF: 0.432

Asia WGS AF: 0.315 AC: 1096 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.72
PhyloP100		-0.55

Splicing

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

Other links and lift over

dbSNP: rs7485331; hg19: chr12-103312619;