chr16-67166010-A-AGGTGCAGGCTTTGCGGGG
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4BS2_Supporting
The NM_001374675.1(HSF4):c.426_443dup(p.Ala145_Gln150dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,474,414 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000035 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000076 ( 1 hom. )
Consequence
HSF4
NM_001374675.1 inframe_insertion
NM_001374675.1 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.507
Genes affected
HSF4 (HGNC:5227): (heat shock transcription factor 4) Heat-shock transcription factors (HSFs) activate heat-shock response genes under conditions of heat or other stresses. HSF4 lacks the carboxyl-terminal hydrophobic repeat which is shared among all vertebrate HSFs and has been suggested to be involved in the negative regulation of DNA binding activity. Two alternatively spliced transcripts encoding distinct isoforms and possessing different transcriptional activity have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_001374675.1.
BS2
High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSF4 | NM_001374675.1 | c.426_443dup | p.Ala145_Gln150dup | inframe_insertion | 4/13 | ENST00000521374.6 | |
HSF4 | NM_001040667.3 | c.426_443dup | p.Ala145_Gln150dup | inframe_insertion | 6/15 | ||
HSF4 | NM_001374674.1 | c.426_443dup | p.Ala145_Gln150dup | inframe_insertion | 4/13 | ||
HSF4 | NM_001538.4 | c.426_443dup | p.Ala145_Gln150dup | inframe_insertion | 6/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSF4 | ENST00000521374.6 | c.426_443dup | p.Ala145_Gln150dup | inframe_insertion | 4/13 | 1 | NM_001374675.1 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000351 AC: 5AN: 142618Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000758 AC: 101AN: 1331796Hom.: 1 Cov.: 34 AF XY: 0.0000898 AC XY: 59AN XY: 656806
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GnomAD4 genome AF: 0.0000351 AC: 5AN: 142618Hom.: 0 Cov.: 32 AF XY: 0.0000435 AC XY: 3AN XY: 68992
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cataract 5 multiple types Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
HSF4-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 13, 2022 | The HSF4 c.426_443dup18 variant is predicted to result in an in-frame duplication (p.Ala145_Gln150dup). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-67199913-A-AGGTGCAGGCTTTGCGGGG). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at