chr16-67165612-G-A

Position:

• chr16-67165612-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001374675.1(HSF4):​c.214G>A​(p.Val72Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.16

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSF4	NM_001374675.1	c.214G>A	p.Val72Met	missense_variant	2/13	ENST00000521374.6
HSF4	NM_001040667.3	c.214G>A	p.Val72Met	missense_variant	4/15
HSF4	NM_001374674.1	c.214G>A	p.Val72Met	missense_variant	2/13
HSF4	NM_001538.4	c.214G>A	p.Val72Met	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSF4	ENST00000521374.6	c.214G>A	p.Val72Met	missense_variant	2/13	1	NM_001374675.1	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2021

The c.214G>A (p.V72M) alteration is located in exon 4 (coding exon 2) of the HSF4 gene. This alteration results from a G to A substitution at nucleotide position 214, causing the valine (V) at amino acid position 72 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.8	.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D;D;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.91, 0.78
MutPred		0.81		Gain of MoRF binding (P = 0.12);Gain of MoRF binding (P = 0.12);Gain of MoRF binding (P = 0.12);.;
MVP		0.85
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr16-67199515;