NM_000277.3:c.969+606G>A

Variant names:

• chr12-102846289-C-T
• rs12425434
• NM_000277.3:c.969+606G>A

Variant summary

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

The NM_000277.3(PAH):​c.969+606G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 152,146 control chromosomes in the GnomAD database, including 5,126 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 0.23 (5126 hom., cov: 32)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0590
• Publications: 3 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.969+606G>A		intron_variant	Intron 9 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.969+606G>A		intron_variant	Intron 10 of 13		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.969+606G>A		intron_variant	Intron 9 of 12	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34926 AN: 152028 Hom.: 5124 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.243

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

GnomAD4 genome AF: 0.230 AC: 34951 AN: 152146 Hom.: 5126 Cov.: 32 AF XY: 0.235 AC XY: 17484 AN XY: 74376

African (AFR) AF: 0.108 AC: 4467 AN: 41526

American (AMR) AF: 0.199 AC: 3050 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 989 AN: 3472

East Asian (EAS) AF: 0.751 AC: 3885 AN: 5172

South Asian (SAS) AF: 0.372 AC: 1792 AN: 4820

European-Finnish (FIN) AF: 0.299 AC: 3167 AN: 10580

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16750 AN: 67968

Other (OTH) AF: 0.244 AC: 516 AN: 2112

Alfa AF: 0.251 Hom.: 1827

Bravo AF: 0.218

Asia WGS AF: 0.472 AC: 1641 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.8
DANN	Benign	0.38
PhyloP100		-0.059
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: rs12425434; hg19: chr12-103240067;