16-67164849-G-A

Variant names:

• chr16-67164849-G-A
• rs552072672
• NM_001374675.1:c.38G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001374675.1(HSF4):​c.38G>A​(p.Gly13Asp) 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. 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: 3.18

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35572115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSF4	NM_001374675.1	c.38G>A	p.Gly13Asp	missense_variant	Exon 1 of 13	ENST00000521374.6	NP_001361604.1
HSF4	NM_001040667.3	c.38G>A	p.Gly13Asp	missense_variant	Exon 3 of 15		NP_001035757.1
HSF4	NM_001374674.1	c.38G>A	p.Gly13Asp	missense_variant	Exon 1 of 13		NP_001361603.1
HSF4	NM_001538.4	c.38G>A	p.Gly13Asp	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.38G>A	p.Gly13Asp	missense_variant	Exon 1 of 13	1	NM_001374675.1	ENSP00000430947.2
ENSG00000265690	ENST00000580114.5	n.*567G>A		non_coding_transcript_exon_variant	Exon 3 of 5	5		ENSP00000464271.1
ENSG00000265690	ENST00000580114.5	n.*567G>A		3_prime_UTR_variant	Exon 3 of 5	5		ENSP00000464271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000453 AC: 1 AN: 220766 Hom.: 0 AF XY: 0.00000814 AC XY: 1 AN XY: 122910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000184

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000171 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 5 multiple types Uncertain:1

Nov 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 13 of the HSF4 protein (p.Gly13Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with HSF4-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	Uncertain	0.42
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.1	.;M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	N;N;.
REVEL	Benign	0.14
Sift	Uncertain	0.013	D;T;.
Sift4G	Benign	0.086	T;T;D
Polyphen		1.0	.;D;D
Vest4		0.47, 0.47
MutPred		0.32		Loss of catalytic residue at G13 (P = 0.0413);Loss of catalytic residue at G13 (P = 0.0413);Loss of catalytic residue at G13 (P = 0.0413);
MVP		0.59
ClinPred		0.96	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.62

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: rs552072672; hg19: chr16-67198752;