rs115335849

Variant names:

• chr16-67164943-C-T
• rs115335849
• NM_001374675.1:c.123+9C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001040667.3(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_001040667.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.191
• 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

ENSG00000265690 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040667.3. 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
	HSF4	NM_001374675.1	MANE Select	c.123+9C>T		intron	N/A	NP_001361604.1
	HSF4	NM_001040667.3		c.123+9C>T		intron	N/A	NP_001035757.1
	HSF4	NM_001374674.1		c.123+9C>T		intron	N/A	NP_001361603.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSF4	ENST00000521374.6	TSL:1 MANE Select	c.123+9C>T		intron	N/A	ENSP00000430947.2
	HSF4	ENST00000584272.5	TSL:1	c.123+9C>T		intron	N/A	ENSP00000463706.1
	ENSG00000265690	ENST00000518227.1	TSL:1	n.*661C>T		non_coding_transcript_exon	Exon 3 of 3	ENSP00000476527.1

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

GnomAD2 exomes AF: 0.0218 AC: 4520 AN: 206952 AF XY: 0.0223

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.: 31 AF XY: 0.0106 AC XY: 7631 AN XY: 717310

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: 53 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: 2 AN: 46850

Middle Eastern (MID) AF: 0.0171 AC: 94 AN: 5502

European-Non Finnish (NFE) AF: 0.000921 AC: 1019 AN: 1106628

Other (OTH) AF: 0.0185 AC: 1104 AN: 59748

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

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: 2 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: 1 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68028

Other (OTH) AF: 0.0369 AC: 78 AN: 2116

Alfa AF: 0.0178 Hom.: 79

Bravo AF: 0.0510

Asia WGS AF: 0.0670 AC: 231 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cataract 5 multiple types (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.94
PhyloP100		-0.19
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs115335849; hg19: chr16-67198846;