8-144474542-G-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2
The NM_003923.3(FOXH1):c.794C>A(p.Ser265Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,610,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S265S) has been classified as Likely benign.
Frequency
Consequence
NM_003923.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOXH1 | NM_003923.3 | c.794C>A | p.Ser265Tyr | missense_variant | 3/3 | ENST00000377317.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOXH1 | ENST00000377317.5 | c.794C>A | p.Ser265Tyr | missense_variant | 3/3 | 1 | NM_003923.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000324 AC: 8AN: 246856Hom.: 0 AF XY: 0.0000521 AC XY: 7AN XY: 134418
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1458688Hom.: 0 Cov.: 35 AF XY: 0.0000234 AC XY: 17AN XY: 725634
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
Holoprosencephaly sequence Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2016 | This variant is present in population databases (rs769660425, ExAC 0.02%) but has not been reported in the literature in individuals with a FOXH1-related disease. This sequence change replaces serine with tyrosine at codon 265 of the FOXH1 protein (p.Ser265Tyr). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tyrosine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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