rs1555549755

Variant names:

• chr16-67164899-GA-G
• rs1555549755
• NM_001374675.1:c.89delA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001374675.1(HSF4):​c.89delA​(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
• Publications: 1 publications found

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]

HSF4 Gene-Disease associations (from GenCC):

• cataract 5 multiple types

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• early-onset lamellar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000265690 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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 15 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 VariationId is 459609.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374675.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSF4	NM_001374675.1	MANE Select	c.89delA	p.Asp30AlafsTer7	frameshift	Exon 1 of 13	NP_001361604.1
	HSF4	NM_001040667.3		c.89delA	p.Asp30AlafsTer7	frameshift	Exon 3 of 15	NP_001035757.1
	HSF4	NM_001374674.1		c.89delA	p.Asp30AlafsTer7	frameshift	Exon 1 of 13	NP_001361603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSF4	ENST00000521374.6	TSL:1 MANE Select	c.89delA	p.Asp30AlafsTer7	frameshift	Exon 1 of 13	ENSP00000430947.2
	HSF4	ENST00000584272.5	TSL:1	c.89delA	p.Asp30AlafsTer7	frameshift	Exon 1 of 13	ENSP00000463706.1
	HSF4	ENST00000434833.6	TSL:1	n.89delA		non_coding_transcript_exon	Exon 1 of 13	ENSP00000403219.2

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

Nov 09, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. While this particular variant has not been reported in the literature, loss-of-function variants in HSF4 are known to be pathogenic (PMID: 24045990). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555549755; hg19: chr16-67198802;