17-58487734-C-T

Variant names:

• chr17-58487734-C-T
• rs576559569
• NM_001080439.3:c.541G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 13/20 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. E181D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: HSF5 NM_001080439.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58
• Publications: 0 publications found

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]

ENSG00000299242 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055048913).
• BS2: High AC in GnomAd4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080439.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSF5	NM_001080439.3	MANE Select	c.541G>A	p.Glu181Lys	missense	Exon 1 of 6	NP_001073908.2	Q4G112-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSF5	ENST00000323777.8	TSL:1 MANE Select	c.541G>A	p.Glu181Lys	missense	Exon 1 of 6	ENSP00000313243.3	Q4G112-1
	ENSG00000299242	ENST00000761905.1		n.146+329C>T		intron	N/A
	ENSG00000299242	ENST00000761906.1		n.168+329C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152124 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000903 AC: 2 AN: 22148 AF XY: 0.000157

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 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.: 0 Cov.: 32 AF XY: 0.0000820 AC XY: 49 AN XY: 597784

African (AFR) AF: 0.0000824 AC: 2 AN: 24286

American (AMR) AF: 0.0000814 AC: 1 AN: 12288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16618

East Asian (EAS) AF: 0.00 AC: 0 AN: 28770

South Asian (SAS) AF: 0.0000193 AC: 1 AN: 51770

European-Finnish (FIN) AF: 0.0000673 AC: 2 AN: 29718

Middle Eastern (MID) AF: 0.00147 AC: 5 AN: 3402

European-Non Finnish (NFE) AF: 0.0000812 AC: 82 AN: 1009580

Other (OTH) AF: 0.000259 AC: 13 AN: 50288

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74416

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.000261 AC: 4 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67980

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.0000881 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.52	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.96	T
PhyloP100		1.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.060	N
REVEL	Benign	0.083
Sift	Uncertain	0.026	D
Sift4G	Benign	0.24	T
Vest4		0.27
MutPred		0.35		Gain of ubiquitination at E181 (P = 0.0077)
MVP		0.22
MPC		1.6
ClinPred		0.087	T
GERP RS		3.9
gMVP		0.50
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs576559569; hg19: chr17-56565095;