chr16-67164925-CTGGAGCCCGG-C

Variant names:

• chr16-67164925-CTGGAGCCCGG-C
• NM_001374675.1:c.117_123+3delGAGCCCGGTG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001374675.1(HSF4):​c.117_123+3delGAGCCCGGTG​(p.Trp39AlafsTer7) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSF4 NM_001374675.1 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.92

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]

ENSG00000265690 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-67164925-CTGGAGCCCGG-C is Pathogenic according to our data. Variant chr16-67164925-CTGGAGCCCGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3727898.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSF4	NM_001374675.1	c.117_123+3delGAGCCCGGTG	p.Trp39AlafsTer7	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 13	ENST00000521374.6	NP_001361604.1
HSF4	NM_001040667.3	c.117_123+3delGAGCCCGGTG	p.Trp39AlafsTer7	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 3 of 15		NP_001035757.1
HSF4	NM_001374674.1	c.117_123+3delGAGCCCGGTG	p.Trp39AlafsTer7	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 13		NP_001361603.1
HSF4	NM_001538.4	c.117_123+3delGAGCCCGGTG	p.Trp39AlafsTer7	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 3 of 15		NP_001529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSF4	ENST00000521374.6	c.117_123+3delGAGCCCGGTG	p.Trp39AlafsTer7	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 13	1	NM_001374675.1	ENSP00000430947.2
ENSG00000265690	ENST00000580114.5	n.*646_*652+3delGAGCCCGGTG		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 5	5		ENSP00000464271.1
ENSG00000265690	ENST00000580114.5	n.*646_*652+3delGAGCCCGGTG		splice_donor_variant, splice_region_variant, 3_prime_UTR_variant, intron_variant	Exon 3 of 5	5		ENSP00000464271.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 5 multiple types Pathogenic:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the deletion of part of exon 3 (c.117_123+3del) of the HSF4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HSF4 are known to be pathogenic (PMID: 15959809). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HSF4-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-67198828;