16-67164943-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The ENST00000518227.1(ENSG00000265690):n.*661C>T variant causes a non coding transcript exon 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

ENSG00000265690
ENST00000518227.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.191

Publications

4 publications found

Variant links:

Genes affected

ENSG00000265690 (HGNC:):

ENSG00000265690 links:

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]

HSF4 Gene-Disease associations (from GenCC):

cataract 5 multiple types
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
early-onset lamellar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HSF4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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	Effect	Exon rank	MANE	Protein	UniProt
HSF4	NM_001374675.1 link	c.123+9C>T	intron_variant	Intron 1 of 12	ENST00000521374.6	NP_001361604.1
HSF4	NM_001040667.3 link	c.123+9C>T	intron_variant	Intron 3 of 14		NP_001035757.1	Q9ULV5-1A0A024R6X7
HSF4	NM_001374674.1 link	c.123+9C>T	intron_variant	Intron 1 of 12		NP_001361603.1
HSF4	NM_001538.4 link	c.123+9C>T	intron_variant	Intron 3 of 14		NP_001529.2	Q9ULV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSF4	ENST00000521374.6 link	c.123+9C>T		intron_variant	Intron 1 of 12	1	NM_001374675.1	ENSP00000430947.2		Q9ULV5-1
ENSG00000265690	ENST00000580114.5 link	n.*652+9C>T		intron_variant	Intron 3 of 4	5		ENSP00000464271.1		J3QRK9

Frequencies

GnomAD3 genomes

AF:

0.0475

AC:

7234

AN:

152142

Hom.:

504

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0218

AC:

4520

AN:

206952

AF XY:

0.0223

show subpopulations

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 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.:

AF XY:

0.0106

AC XY:

7631

AN XY:

717310

show subpopulations

African (AFR)

AF:

0.155

AC:

5137

AN:

33104

American (AMR)

AF:

0.0124

AC:

535

AN:

43180

Ashkenazi Jewish (ASJ)

AF:

0.00206

AC:

AN:

25678

East Asian (EAS)

AF:

0.0128

AC:

502

AN:

39102

South Asian (SAS)

AF:

0.0636

AC:

5354

AN:

84126

European-Finnish (FIN)

AF:

0.0000427

AC:

AN:

46850

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

5502

European-Non Finnish (NFE)

AF:

0.000921

AC:

1019

AN:

1106628

Other (OTH)

AF:

0.0185

AC:

1104

AN:

59748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

651

1302

1952

2603

3254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

250

500

750

1000

1250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0476

AC:

7251

AN:

152260

Hom.:

505

Cov.:

AF XY:

0.0467

AC XY:

3476

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.153

AC:

6354

AN:

41542

American (AMR)

AF:

0.0224

AC:

343

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.0200

AC:

103

AN:

5150

South Asian (SAS)

AF:

0.0596

AC:

287

AN:

4818

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

68028

Other (OTH)

AF:

0.0369

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

313

625

938

1250

1563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0178

Hom.:

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

LINK: link

Submissions by phenotype

Cataract 5 multiple types

Benign:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:2

Jul 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

-0.19

PromoterAI

-0.035

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over