16-67169874-G-T

Variant names:

• chr16-67169874-G-T
• rs11642409
• ENST00000434833.6:n.*516G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000434833.6(HSF4):​n.*516G>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 0.00699 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 ENST00000434833.6 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.893
• Publications: 4 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000434833.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSF4	NM_001374675.1	MANE Select	c.*89G>T		3_prime_UTR	Exon 13 of 13	NP_001361604.1
	HSF4	NM_001040667.3		c.*89G>T		3_prime_UTR	Exon 15 of 15	NP_001035757.1
	HSF4	NM_001374674.1		c.*89G>T		3_prime_UTR	Exon 13 of 13	NP_001361603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSF4	ENST00000434833.6	TSL:1	n.*516G>T		non_coding_transcript_exon	Exon 13 of 13	ENSP00000403219.2
	HSF4	ENST00000521624.5	TSL:1	n.*312G>T		non_coding_transcript_exon	Exon 11 of 11	ENSP00000428161.1
	HSF4	ENST00000521374.6	TSL:1 MANE Select	c.*89G>T		3_prime_UTR	Exon 13 of 13	ENSP00000430947.2

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

African (AFR) AF: 0.00145 AC: 43 AN: 29584

American (AMR) AF: 0.00185 AC: 82 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.0000806 AC: 2 AN: 24810

East Asian (EAS) AF: 0.00 AC: 0 AN: 38788

South Asian (SAS) AF: 0.000963 AC: 79 AN: 82030

European-Finnish (FIN) AF: 0.0196 AC: 943 AN: 48024

Middle Eastern (MID) AF: 0.00153 AC: 8 AN: 5224

European-Non Finnish (NFE) AF: 0.00810 AC: 7466 AN: 922164

Other (OTH) AF: 0.00522 AC: 279 AN: 53430

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

African (AFR) AF: 0.00157 AC: 65 AN: 41290

American (AMR) AF: 0.00262 AC: 40 AN: 15252

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4788

European-Finnish (FIN) AF: 0.0215 AC: 221 AN: 10264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00793 AC: 539 AN: 67968

Other (OTH) AF: 0.00191 AC: 4 AN: 2090

Alfa AF: 0.00613 Hom.: 3

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

Jan 12, 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:1

Jun 28, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.82
PhyloP100		0.89
PromoterAI		0.087	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs11642409; hg19: chr16-67203777; COSMIC: COSV106332776; COSMIC: COSV106332776;