NM_001374675.1:c.69G>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_001374675.1(HSF4):c.69G>T(p.Lys23Asn) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HSF4
NM_001374675.1 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.61

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 links:

ENSG00000265690 (HGNC:):

ENSG00000265690 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

PP5

Variant 16-67164880-G-T is Pathogenic according to our data. Variant chr16-67164880-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2137837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-67164880-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSF4	NM_001374675.1 link	c.69G>T	p.Lys23Asn	missense_variant	Exon 1 of 13	ENST00000521374.6	NP_001361604.1
HSF4	NM_001040667.3 link	c.69G>T	p.Lys23Asn	missense_variant	Exon 3 of 15		NP_001035757.1	Q9ULV5-1A0A024R6X7
HSF4	NM_001374674.1 link	c.69G>T	p.Lys23Asn	missense_variant	Exon 1 of 13		NP_001361603.1
HSF4	NM_001538.4 link	c.69G>T	p.Lys23Asn	missense_variant	Exon 3 of 15		NP_001529.2	Q9ULV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSF4	ENST00000521374.6 link	c.69G>T	p.Lys23Asn	missense_variant	Exon 1 of 13	1	NM_001374675.1	ENSP00000430947.2	Q9ULV5-1
ENSG00000265690	ENST00000580114.5 link	n.*598G>T		non_coding_transcript_exon_variant	Exon 3 of 5	5		ENSP00000464271.1	J3QRK9
ENSG00000265690	ENST00000580114.5 link	n.*598G>T		3_prime_UTR_variant	Exon 3 of 5	5		ENSP00000464271.1	J3QRK9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1455628

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724002

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cataract 5 multiple types

Pathogenic:1

Mar 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 23 of the HSF4 protein (p.Lys23Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital cataracts (PMID: 24637349). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;D;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.2

.;M;M

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-4.6

D;D;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0040

D;D;.

Sift4G

Uncertain

0.015

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.98, 0.87

MutPred

0.53

Loss of ubiquitination at K23 (P = 0.0141);Loss of ubiquitination at K23 (P = 0.0141);Loss of ubiquitination at K23 (P = 0.0141);

MVP

0.88

ClinPred

1.0

GERP RS

4.3

Varity_R

0.99

gMVP

0.93

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over