rs115335849

Positions:

• chr16-67164943-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001374675.1(HSF4):​c.123+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,596,178 control chromosomes in the GnomAD database, including 1,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (505 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (698 hom.)
• Consequence: HSF4 NM_001374675.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.191

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 16-67164943-C-T is Benign according to our data. Variant chr16-67164943-C-T is described in ClinVar as [Benign]. Clinvar id is 258163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSF4	NM_001374675.1	c.123+9C>T		intron_variant		ENST00000521374.6
HSF4	NM_001040667.3	c.123+9C>T		intron_variant
HSF4	NM_001374674.1	c.123+9C>T		intron_variant
HSF4	NM_001538.4	c.123+9C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSF4	ENST00000521374.6	c.123+9C>T		intron_variant		1	NM_001374675.1	P4

Frequencies

GnomAD3 genomes AF: 0.0475 AC: 7234 AN: 152142 Hom.: 504 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.0601

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0349

GnomAD3 exomes AF: 0.0218 AC: 4520 AN: 206952 Hom.: 222 AF XY: 0.0223 AC XY: 2559 AN XY: 114750

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.00158

Gnomad EAS exome AF: 0.0141

Gnomad SAS exome AF: 0.0692

Gnomad FIN exome AF: 0.0000649

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.00956 AC: 13800 AN: 1443918 Hom.: 698 Cov.: 31 AF XY: 0.0106 AC XY: 7631 AN XY: 717310

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00206

Gnomad4 EAS exome AF: 0.0128

Gnomad4 SAS exome AF: 0.0636

Gnomad4 FIN exome AF: 0.0000427

Gnomad4 NFE exome AF: 0.000921

Gnomad4 OTH exome AF: 0.0185

GnomAD4 genome AF: 0.0476 AC: 7251 AN: 152260 Hom.: 505 Cov.: 32 AF XY: 0.0467 AC XY: 3476 AN XY: 74454

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0224

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0200

Gnomad4 SAS AF: 0.0596

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0133 Hom.: 40

Bravo AF: 0.0510

Asia WGS AF: 0.0670 AC: 231 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 5 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs115335849; hg19: chr16-67198846;