rs1718301

Variant names:

• chr12-102877415-G-A
• rs1718301
• NM_000277.3:c.441+47C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102877415-G-A
• chr12-102877415-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP7

This summary comes from the ClinGen Evidence Repository: This c.441+47C>T variant in PAH is widely found in population databases at a frequency of 0.372401 in ExAC. This intronic variant is not predicted to have a splice-altering consequence. In summary, this variant meets criteria to be classified as a benign for PAH. PAH-specific ACMG/AMP criteria applied: BP7, BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229547/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.38 (11349 hom., cov: 30)
  • Exomes 𝑓: 0.41 (99780 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Benign reviewed by expert panel B:7 O:1
• Conservation: PhyloP100: -1.57

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]

LOC124902999 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.441+47C>T		intron_variant	Intron 4 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.441+47C>T		intron_variant	Intron 5 of 13		NP_001341233.1
PAH	XM_017019370.2	c.441+47C>T		intron_variant	Intron 4 of 6		XP_016874859.1
LOC124902999	XR_007063428.1	n.808-2464G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.441+47C>T		intron_variant	Intron 4 of 12	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 56924 AN: 151588 Hom.: 11340 Cov.: 30

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.379

GnomAD3 exomes AF: 0.372 AC: 93499 AN: 251282 Hom.: 19054 AF XY: 0.379 AC XY: 51498 AN XY: 135814

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.259

Gnomad ASJ exome AF: 0.335

Gnomad EAS exome AF: 0.103

Gnomad SAS exome AF: 0.366

Gnomad FIN exome AF: 0.531

Gnomad NFE exome AF: 0.437

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.414 AC: 462000 AN: 1116288 Hom.: 99780 Cov.: 15 AF XY: 0.413 AC XY: 236451 AN XY: 572126

Gnomad4 AFR exome AF: 0.285

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.336

Gnomad4 EAS exome AF: 0.134

Gnomad4 SAS exome AF: 0.368

Gnomad4 FIN exome AF: 0.531

Gnomad4 NFE exome AF: 0.440

Gnomad4 OTH exome AF: 0.397

GnomAD4 genome AF: 0.375 AC: 56951 AN: 151706 Hom.: 11349 Cov.: 30 AF XY: 0.378 AC XY: 27999 AN XY: 74090

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.545

Gnomad4 NFE AF: 0.439

Gnomad4 OTH AF: 0.381

Alfa AF: 0.396 Hom.: 6272

Bravo AF: 0.354

Asia WGS AF: 0.264 AC: 918 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Benign:4

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2022

ClinGen PAH Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

This c.441+47C>T variant in PAH is widely found in population databases at a frequency of 0.372401 in ExAC. This intronic variant is not predicted to have a splice-altering consequence. In summary, this variant meets criteria to be classified as a benign for PAH. PAH-specific ACMG/AMP criteria applied: BP7, BA1. -

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.30
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1718301; hg19: chr12-103271193; COSMIC: COSV61016577; COSMIC: COSV61016577;