17-58487734-C-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001080439.3(HSF5):​c.541G>T​(p.Glu181*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000815 in 1,226,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: HSF5 NM_001080439.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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>T	p.Glu181*	stop_gained	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>T	p.Glu181*	stop_gained	Exon 1 of 6	ENSP00000313243.3	Q4G112-1
	ENSG00000299242	ENST00000761905.1		n.146+329C>A		intron	N/A
	ENSG00000299242	ENST00000761906.1		n.168+329C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.15e-7 AC: 1 AN: 1226720 Hom.: 0 Cov.: 32 AF XY: 0.00000167 AC XY: 1 AN XY: 597784

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24286

American (AMR) AF: 0.00 AC: 0 AN: 12288

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

East Asian (EAS) AF: 0.0000348 AC: 1 AN: 28770

South Asian (SAS) AF: 0.00 AC: 0 AN: 51770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3402

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1009580

Other (OTH) AF: 0.00 AC: 0 AN: 50288

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.60	D
PhyloP100		1.6
Vest4		0.16
GERP RS		3.9

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;