rs1555549755

chr16-67164899-GA-G

Variant summary

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

The NM_001374675.1(HSF4):c.89del(p.Asp30AlafsTer7) variant causes a frameshift 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. D30D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSF4 NM_001374675.1 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 39 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-67164899-GA-G is Pathogenic according to our data. Variant chr16-67164899-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 459609.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSF4	NM_001374675.1	c.89del	p.Asp30AlafsTer7	frameshift_variant	1/13	ENST00000521374.6
HSF4	NM_001040667.3	c.89del	p.Asp30AlafsTer7	frameshift_variant	3/15
HSF4	NM_001374674.1	c.89del	p.Asp30AlafsTer7	frameshift_variant	1/13
HSF4	NM_001538.4	c.89del	p.Asp30AlafsTer7	frameshift_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSF4	ENST00000521374.6	c.89del	p.Asp30AlafsTer7	frameshift_variant	1/13	1	NM_001374675.1	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 5 multiple types Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 09, 2017

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in HSF4 are known to be pathogenic (PMID: 24045990). This sequence change deletes 1 nucleotide from exon 3 of the HSF4 mRNA (c.89delA), causing a frameshift at codon 30. This creates a premature translational stop signal (p.Asp30Alafs*7) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555549755; hg19: chr16-67198802;