Genetic Variant HSF4:p.Glu11Gly (chr16-67164843-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001374675.1(HSF4):c.32A>G(p.Glu11Gly) 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. 12/21 in silico tools predict a benign outcome for this variant. 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. E11D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

HSF4
NM_001374675.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27

Publications

1 publications found

Variant links:

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]

HSF4 Gene-Disease associations (from GenCC):

cataract 5 multiple types
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
early-onset lamellar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HSF4 links:

ENSG00000265690 (HGNC:):

ENSG00000265690 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31150115).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374675.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSF4	NM_001374675.1	MANE Select	c.32A>G	p.Glu11Gly	missense	Exon 1 of 13	NP_001361604.1	Q9ULV5-1
HSF4	NM_001040667.3		c.32A>G	p.Glu11Gly	missense	Exon 3 of 15	NP_001035757.1	Q9ULV5-1
HSF4	NM_001374674.1		c.32A>G	p.Glu11Gly	missense	Exon 1 of 13	NP_001361603.1	Q9ULV5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSF4	ENST00000521374.6	TSL:1 MANE Select	c.32A>G	p.Glu11Gly	missense	Exon 1 of 13	ENSP00000430947.2	Q9ULV5-1
HSF4	ENST00000584272.5	TSL:1	c.32A>G	p.Glu11Gly	missense	Exon 1 of 13	ENSP00000463706.1	Q9ULV5-2
HSF4	ENST00000434833.6	TSL:1	n.32A>G		non_coding_transcript_exon	Exon 1 of 13	ENSP00000403219.2	E7EWW4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cataract 5 multiple types (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0072

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

M_CAP

Benign

0.033

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.73

MutationAssessor

Benign

-0.30

PhyloP100

3.3

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.45

REVEL

Benign

0.13

Sift

Uncertain

0.025

Sift4G

Benign

0.28

Polyphen

1.0

Vest4

0.19

MutPred

0.39

Loss of solvent accessibility (P = 0.0098)

MVP

0.57

ClinPred

0.91

GERP RS

4.7

PromoterAI

-0.040

Neutral

(source)

Varity_R

0.14

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over