dbSNP rs121909050: HSF4:p.Ile86Val (chr16-67165742-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_001374675.1(HSF4):c.256A>G(p.Ile86Val) variant causes a missense change. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I86T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

HSF4
NM_001374675.1 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.62

Publications

8 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: G2P, Labcorp Genetics (formerly Invitae)
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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-67165742-A-G is Pathogenic according to our data. Variant chr16-67165742-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7095.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.30534673). . Strength limited to SUPPORTING due to the PP5.

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
HSF4	NM_001374675.1	MANE Select	c.256A>G	p.Ile86Val	missense	Exon 3 of 13	NP_001361604.1
HSF4	NM_001040667.3		c.256A>G	p.Ile86Val	missense	Exon 5 of 15	NP_001035757.1
HSF4	NM_001374674.1		c.256A>G	p.Ile86Val	missense	Exon 3 of 13	NP_001361603.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HSF4	ENST00000521374.6	TSL:1 MANE Select	c.256A>G	p.Ile86Val	missense	Exon 3 of 13	ENSP00000430947.2
HSF4	ENST00000584272.5	TSL:1	c.256A>G	p.Ile86Val	missense	Exon 3 of 13	ENSP00000463706.1
HSF4	ENST00000434833.6	TSL:1	n.256A>G		non_coding_transcript_exon	Exon 3 of 13	ENSP00000403219.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000764

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Cataract 5 multiple types

Pathogenic:1

Jul 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.30

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.057

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.043

MetaRNN

Benign

0.31

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

-0.39

PhyloP100

3.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.49

REVEL

Uncertain

0.49

Sift

Benign

0.29

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.50

MutPred

0.66

Gain of disorder (P = 0.0635)

MVP

0.71

ClinPred

0.82

GERP RS

4.9

PromoterAI

-0.0081

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.28

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over