chr5-154475888-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_004821.3(HAND1):c.566C>T(p.Pro189Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,970 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P189S) has been classified as Uncertain significance.
Frequency
Consequence
NM_004821.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HAND1 | NM_004821.3 | c.566C>T | p.Pro189Leu | missense_variant | 2/2 | ENST00000231121.3 | |
HAND1 | XM_005268531.2 | c.563C>T | p.Pro188Leu | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HAND1 | ENST00000231121.3 | c.566C>T | p.Pro189Leu | missense_variant | 2/2 | 1 | NM_004821.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000243 AC: 37AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 250980Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135740
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461624Hom.: 1 Cov.: 30 AF XY: 0.0000138 AC XY: 10AN XY: 727140
GnomAD4 genome ? AF: 0.000236 AC: 36AN: 152346Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20AN XY: 74500
ClinVar
Submissions by phenotype
Hypoplastic left heart syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 189 of the HAND1 protein (p.Pro189Leu). This variant is present in population databases (rs147677474, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with HAND1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1495405). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at