chr16-67164851-C-A

Position:

• chr16-67164851-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001374675.1(HSF4):​c.40C>A​(p.Pro14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: 1.35

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21634609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSF4	NM_001374675.1	c.40C>A	p.Pro14Thr	missense_variant	1/13	ENST00000521374.6
HSF4	NM_001040667.3	c.40C>A	p.Pro14Thr	missense_variant	3/15
HSF4	NM_001374674.1	c.40C>A	p.Pro14Thr	missense_variant	1/13
HSF4	NM_001538.4	c.40C>A	p.Pro14Thr	missense_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSF4	ENST00000521374.6	c.40C>A	p.Pro14Thr	missense_variant	1/13	1	NM_001374675.1	P4

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

Cataract 5 multiple types Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 14 of the HSF4 protein (p.Pro14Thr). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HSF4 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.010	T;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.76	N;N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.49	N;N;.
REVEL	Benign	0.10
Sift	Benign	0.088	T;T;.
Sift4G	Benign	0.25	T;T;T
Polyphen		1.0, 1.0	.;D;D
Vest4		0.25, 0.29
MutPred		0.27		Gain of phosphorylation at P14 (P = 0.0229);Gain of phosphorylation at P14 (P = 0.0229);Gain of phosphorylation at P14 (P = 0.0229);
MVP		0.52
ClinPred		0.63	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-67198754;