rs937476

Variant names:

• chr12-102853786-T-A
• rs937476
• NM_000277.3:c.707-836A>T

Variant summary

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

The NM_000277.3(PAH):​c.707-836A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 152,036 control chromosomes in the GnomAD database, including 13,357 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 0.41 (13357 hom., cov: 32)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.707-836A>T		intron_variant	Intron 6 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.707-836A>T		intron_variant	Intron 7 of 13		NP_001341233.1
PAH	XM_017019370.2	c.*999A>T		downstream_gene_variant			XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.707-836A>T		intron_variant	Intron 6 of 12	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.692-836A>T		intron_variant	Intron 7 of 13	5		ENSP00000303500.2

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62629 AN: 151918 Hom.: 13345 Cov.: 32

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.0635

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.405

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

GnomAD4 genome AF: 0.412 AC: 62672 AN: 152036 Hom.: 13357 Cov.: 32 AF XY: 0.413 AC XY: 30701 AN XY: 74310

Gnomad4 AFR AF: 0.439

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.341

Gnomad4 EAS AF: 0.0637

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.511

Gnomad4 NFE AF: 0.432

Gnomad4 OTH AF: 0.406

Alfa AF: 0.432 Hom.: 1797

Bravo AF: 0.398

Asia WGS AF: 0.278 AC: 967 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.71
DANN	Benign	0.61

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: rs937476; hg19: chr12-103247564;