12-102904739-A-G

Variant names:

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

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+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
• 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: Benign. The variant received -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.

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>C		intron	N/A	NP_000268.1	P00439
	PAH	NM_001354304.2		c.168+8052T>C		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>C		intron	N/A	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.264+8052T>C		intron	N/A
	PAH	ENST00000906695.1		c.168+8052T>C		intron	N/A	ENSP00000576754.1

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

GnomAD2 exomes AF: 0.369 AC: 81491 AN: 221084 AF XY: 0.355

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 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

African (AFR) AF: 0.681 AC: 6627 AN: 9732

American (AMR) AF: 0.541 AC: 18024 AN: 33322

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 3909 AN: 11198

East Asian (EAS) AF: 0.220 AC: 2856 AN: 13004

South Asian (SAS) AF: 0.327 AC: 20983 AN: 64152

European-Finnish (FIN) AF: 0.234 AC: 3876 AN: 16592

Middle Eastern (MID) AF: 0.327 AC: 908 AN: 2780

European-Non Finnish (NFE) AF: 0.323 AC: 60366 AN: 186684

Other (OTH) AF: 0.340 AC: 5450 AN: 16050

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

African (AFR) AF: 0.686 AC: 28451 AN: 41450

American (AMR) AF: 0.510 AC: 7789 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1327 AN: 3466

East Asian (EAS) AF: 0.228 AC: 1176 AN: 5160

South Asian (SAS) AF: 0.339 AC: 1628 AN: 4804

European-Finnish (FIN) AF: 0.224 AC: 2368 AN: 10552

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22650 AN: 67972

Other (OTH) AF: 0.415 AC: 874 AN: 2108

Alfa AF: 0.371 Hom.: 35149

Bravo AF: 0.472

Asia WGS AF: 0.310 AC: 1078 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.65
DANN	Benign	0.30
PhyloP100		-2.4
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: rs1522307; hg19: chr12-103298517; COSMIC: COSV61019171;