16-67164888-C-A

Variant names:

• chr16-67164888-C-A
• rs1308348079
• NM_001374675.1:c.77C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001374675.1(HSF4):​c.77C>A​(p.Ala26Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A26S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSF4 NM_001374675.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSF4	NM_001374675.1	c.77C>A	p.Ala26Glu	missense_variant	Exon 1 of 13	ENST00000521374.6	NP_001361604.1
HSF4	NM_001040667.3	c.77C>A	p.Ala26Glu	missense_variant	Exon 3 of 15		NP_001035757.1
HSF4	NM_001374674.1	c.77C>A	p.Ala26Glu	missense_variant	Exon 1 of 13		NP_001361603.1
HSF4	NM_001538.4	c.77C>A	p.Ala26Glu	missense_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.77C>A	p.Ala26Glu	missense_variant	Exon 1 of 13	1	NM_001374675.1	ENSP00000430947.2
ENSG00000265690	ENST00000580114.5	n.*606C>A		non_coding_transcript_exon_variant	Exon 3 of 5	5		ENSP00000464271.1
ENSG00000265690	ENST00000580114.5	n.*606C>A		3_prime_UTR_variant	Exon 3 of 5	5		ENSP00000464271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.77C>A (p.A26E) alteration is located in exon 3 (coding exon 1) of the HSF4 gene. This alteration results from a C to A substitution at nucleotide position 77, causing the alanine (A) at amino acid position 26 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;D;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.14	.;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Uncertain	0.50
Sift	Benign	0.095	T;D;.
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.39, 0.43
MutPred		0.47		Loss of ubiquitination at K23 (P = 0.0573);Loss of ubiquitination at K23 (P = 0.0573);Loss of ubiquitination at K23 (P = 0.0573);
MVP		0.79
ClinPred		0.92	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1308348079; hg19: chr16-67198791; COSMIC: COSV50457537; COSMIC: COSV50457537;