rs62508624
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000277.3(PAH):c.707-7A>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00504 in 1,613,810 control chromosomes in the GnomAD database, including 334 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Consequence
NM_000277.3 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.707-7A>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000553106.6 | |||
PAH | NM_001354304.2 | c.707-7A>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.707-7A>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000277.3 | P1 | |||
PAH | ENST00000307000.7 | c.692-7A>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | |||||
PAH | ENST00000549247.6 | n.459A>T | non_coding_transcript_exon_variant | 1/6 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0265 AC: 4027AN: 151974Hom.: 175 Cov.: 32
GnomAD3 exomes AF: 0.00715 AC: 1789AN: 250224Hom.: 64 AF XY: 0.00549 AC XY: 743AN XY: 135262
GnomAD4 exome AF: 0.00282 AC: 4115AN: 1461718Hom.: 159 Cov.: 32 AF XY: 0.00252 AC XY: 1831AN XY: 727142
GnomAD4 genome ? AF: 0.0265 AC: 4026AN: 152092Hom.: 175 Cov.: 32 AF XY: 0.0249 AC XY: 1849AN XY: 74362
ClinVar
Submissions by phenotype
Phenylketonuria Benign:5
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 21, 2022 | - - |
Benign, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 10, 2018 | PAH-specific ACMG/AMP criteria applied: BA1: Highest MAF=0.10514 in 1000G. 35 homozygotes in ExAC; BP4: HSF: No significant splicing motif alteration detected. This mutation has probably no impact on splicing. CADD=1.163344. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1, BP4). - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 14, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not provided Benign:4Other:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 02, 2015 | - - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 24, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2019 | This variant is associated with the following publications: (PMID: 2666653, 27884173) - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 14, 2017 | Variant summary: c.707-7A>T in PAH gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.008876 (1049/ 118182 chrs tested), predominantly in individuals of African descent (0.08901; 910/ 10224 chrs tested), including 33 homozygotes. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0079 suggesting that it is a benign polymorphism. The variant of interest has been reported in PKU individuals without strong evidence for causality, but is cited as Benign by a reputable database/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 25, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at