rs199599175
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000709.4(BCKDHA):c.757G>A(p.Ala253Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A253G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000709.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCKDHA | NM_000709.4 | c.757G>A | p.Ala253Thr | missense_variant | 6/9 | ENST00000269980.7 | |
BCKDHA | NM_001164783.2 | c.757G>A | p.Ala253Thr | missense_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHA | ENST00000269980.7 | c.757G>A | p.Ala253Thr | missense_variant | 6/9 | 1 | NM_000709.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251438Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135904
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727240
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152286Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74470
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2022 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BCKDHA protein function. ClinVar contains an entry for this variant (Variation ID: 558191). This variant is also known as A209T. This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 8161368, 16786533, 17922217). This variant is present in population databases (rs199599175, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 253 of the BCKDHA protein (p.Ala253Thr). - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 05, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 04, 2018 | - - |
Maple syrup urine disease type 1A Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 31, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at