chr16-67165554-C-A

Position:

• chr16-67165554-C-A

Variant summary

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

The NM_001374675.1(HSF4):​c.156C>A​(p.Ser52Arg) 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: 0.0640

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33339733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSF4	NM_001374675.1	c.156C>A	p.Ser52Arg	missense_variant	2/13	ENST00000521374.6
HSF4	NM_001040667.3	c.156C>A	p.Ser52Arg	missense_variant	4/15
HSF4	NM_001374674.1	c.156C>A	p.Ser52Arg	missense_variant	2/13
HSF4	NM_001538.4	c.156C>A	p.Ser52Arg	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSF4	ENST00000521374.6	c.156C>A	p.Ser52Arg	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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2022

Variant summary: HSF4 c.156C>A (p.Ser52Arg) results in a non-conservative amino acid change located in the Heat shock factor (HSF)-type, DNA-binding (IPR000232) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249096 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.156C>A in individuals affected with Cataract 5 Multiple Types and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;D;.;.
Eigen	Benign	-0.019
Eigen_PC	Benign	0.068
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.86	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.45	.;N;N;.
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N;N;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.13	T;D;.;D
Sift4G	Uncertain	0.011	D;D;D;T
Polyphen		0.81, 0.90	.;P;P;.
Vest4		0.47, 0.52
MutPred		0.34		Loss of ubiquitination at K56 (P = 0.0362);Loss of ubiquitination at K56 (P = 0.0362);Loss of ubiquitination at K56 (P = 0.0362);.;
MVP		0.73
ClinPred		0.82	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.26

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: chr16-67199457;