Genetic Variant HSF5:p.Glu181Lys (chr17-58487734-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001080439.3(HSF5):c.541G>A(p.Glu181Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000935 in 1,378,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

HSF5
NM_001080439.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.58

Variant links:

Genes affected

HSF5 (HGNC:26862): (heat shock transcription factor 5) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

HSF5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.055048913).

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSF5	NM_001080439.3 link	c.541G>A	p.Glu181Lys	missense_variant	Exon 1 of 6	ENST00000323777.8	NP_001073908.2	Q4G112-1
HSF5	XM_011524283.2 link	c.541G>A	p.Glu181Lys	missense_variant	Exon 1 of 6		XP_011522585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSF5	ENST00000323777.8 link	c.541G>A	p.Glu181Lys	missense_variant	Exon 1 of 6	1	NM_001080439.3	ENSP00000313243.3		Q4G112-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.0000903

AC:

AN:

22148

Hom.:

AF XY:

0.000157

AC XY:

AN XY:

12708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000613

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000827

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000864

AC:

106

AN:

1226720

Hom.:

Cov.:

AF XY:

0.0000820

AC XY:

AN XY:

597784

show subpopulations

Gnomad4 AFR exome

AF:

0.0000824

Gnomad4 AMR exome

AF:

0.0000814

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000193

Gnomad4 FIN exome

AF:

0.0000673

Gnomad4 NFE exome

AF:

0.0000812

Gnomad4 OTH exome

AF:

0.000259

GnomAD4 genome

AF:

0.000151

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.0000881

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.541G>A (p.E181K) alteration is located in exon 1 (coding exon 1) of the HSF5 gene. This alteration results from a G to A substitution at nucleotide position 541, causing the glutamic acid (E) at amino acid position 181 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.52

M_CAP

Benign

0.017

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.96

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.060

REVEL

Benign

0.083

Sift

Uncertain

0.026

Sift4G

Benign

0.24

Vest4

0.27

MutPred

0.35

Gain of ubiquitination at E181 (P = 0.0077);

MVP

0.22

MPC

1.6

ClinPred

0.087

GERP RS

3.9

gMVP

0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over