rs11642409

chr16-67169874-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374675.1(HSF4):c.*89G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00699 in 1,399,744 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (50 hom.)
• Consequence: HSF4 NM_001374675.1 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.893

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-67169874-G-T is Benign according to our data. Variant chr16-67169874-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 320193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00583 (883/151482) while in subpopulation NFE AF= 0.00793 (539/67968). AF 95% confidence interval is 0.00738. There are 2 homozygotes in gnomad4. There are 467 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 883 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSF4	NM_001374675.1	c.*89G>T		3_prime_UTR_variant	13/13	ENST00000521374.6
HSF4	NM_001040667.3	c.*89G>T		3_prime_UTR_variant	15/15
HSF4	NM_001374674.1	c.*89G>T		3_prime_UTR_variant	13/13
HSF4	NM_001538.4	c.*89G>T		3_prime_UTR_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSF4	ENST00000521374.6	c.*89G>T		3_prime_UTR_variant	13/13	1	NM_001374675.1	P4

Frequencies

GnomAD3 genomes AF: 0.00583 AC: 883 AN: 151434 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00158

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000833

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00794

Gnomad OTH AF: 0.00193

GnomAD4 exome AF: 0.00713 AC: 8902 AN: 1248262 Hom.: 50 Cov.: 19 AF XY: 0.00691 AC XY: 4356 AN XY: 630662

Gnomad4 AFR exome AF: 0.00145

Gnomad4 AMR exome AF: 0.00185

Gnomad4 ASJ exome AF: 0.0000806

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000963

Gnomad4 FIN exome AF: 0.0196

Gnomad4 NFE exome AF: 0.00810

Gnomad4 OTH exome AF: 0.00522

GnomAD4 genome AF: 0.00583 AC: 883 AN: 151482 Hom.: 2 Cov.: 32 AF XY: 0.00632 AC XY: 467 AN XY: 73912

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0215

Gnomad4 NFE AF: 0.00793

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00684 Hom.: 1

Bravo AF: 0.00443

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 5 multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	14
Dann	Benign	0.82

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11642409; hg19: chr16-67203777;