NM_001374675.1:c.1476C>A

Variant names:

• chr16-67169782-C-A
• rs367756178
• NM_001374675.1:c.1476C>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001374675.1(HSF4):​c.1476C>A​(p.Pro492Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,613,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: HSF4 NM_001374675.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.86
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.012).
• BP6: Variant 16-67169782-C-A is Benign according to our data. Variant chr16-67169782-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 320191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000282 (43/152298) while in subpopulation AMR AF = 0.00118 (18/15306). AF 95% confidence interval is 0.00076. There are 1 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374675.1. 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.1476C>A	p.Pro492Pro	synonymous	Exon 13 of 13	NP_001361604.1	Q9ULV5-1
	HSF4	NM_001040667.3		c.1476C>A	p.Pro492Pro	synonymous	Exon 15 of 15	NP_001035757.1	Q9ULV5-1
	HSF4	NM_001374674.1		c.1386C>A	p.Pro462Pro	synonymous	Exon 13 of 13	NP_001361603.1	Q9ULV5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSF4	ENST00000521374.6	TSL:1 MANE Select	c.1476C>A	p.Pro492Pro	synonymous	Exon 13 of 13	ENSP00000430947.2	Q9ULV5-1
	HSF4	ENST00000584272.5	TSL:1	c.1386C>A	p.Pro462Pro	synonymous	Exon 13 of 13	ENSP00000463706.1	Q9ULV5-2
	HSF4	ENST00000434833.6	TSL:1	n.*424C>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000403219.2	E7EWW4

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000328 AC: 81 AN: 246706 AF XY: 0.000371

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000332

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000276 AC: 403 AN: 1460860 Hom.: 0 Cov.: 33 AF XY: 0.000337 AC XY: 245 AN XY: 726748

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86256

European-Finnish (FIN) AF: 0.0000572 AC: 3 AN: 52422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000269 AC: 299 AN: 1111994

Other (OTH) AF: 0.000265 AC: 16 AN: 60386

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74486

African (AFR) AF: 0.0000241 AC: 1 AN: 41564

American (AMR) AF: 0.00118 AC: 18 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000317

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cataract 5 multiple types (2)
-	-	1	HSF4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.3
DANN	Benign	0.93
PhyloP100		-1.9
PromoterAI		0.21	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs367756178; hg19: chr16-67203685;