16-67165456-C-G

Variant names:

• chr16-67165456-C-G
• rs115471631
• NM_001374675.1:c.124-66C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374675.1(HSF4):​c.124-66C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00784 in 1,409,102 control chromosomes in the GnomAD database, including 593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (339 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (254 hom.)
• Consequence: HSF4 NM_001374675.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.882
• 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

ENSG00000265690 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-67165456-C-G is Benign according to our data. Variant chr16-67165456-C-G is described in ClinVar as Benign. ClinVar VariationId is 1271790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

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.124-66C>G		intron	N/A	NP_001361604.1	Q9ULV5-1
	HSF4	NM_001040667.3		c.124-66C>G		intron	N/A	NP_001035757.1	Q9ULV5-1
	HSF4	NM_001374674.1		c.124-66C>G		intron	N/A	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.124-66C>G		intron	N/A	ENSP00000430947.2	Q9ULV5-1
	HSF4	ENST00000584272.5	TSL:1	c.124-66C>G		intron	N/A	ENSP00000463706.1	Q9ULV5-2
	ENSG00000265690	ENST00000518227.1	TSL:1	n.*1174C>G		non_coding_transcript_exon	Exon 3 of 3	ENSP00000476527.1	V9GY91

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5515 AN: 152114 Hom.: 337 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0258

GnomAD4 exome AF: 0.00439 AC: 5516 AN: 1256870 Hom.: 254 Cov.: 19 AF XY: 0.00391 AC XY: 2485 AN XY: 635262

African (AFR) AF: 0.134 AC: 3892 AN: 29150

American (AMR) AF: 0.00909 AC: 399 AN: 43880

Ashkenazi Jewish (ASJ) AF: 0.00331 AC: 82 AN: 24782

East Asian (EAS) AF: 0.00 AC: 0 AN: 38746

South Asian (SAS) AF: 0.000292 AC: 24 AN: 82172

European-Finnish (FIN) AF: 0.0000194 AC: 1 AN: 51658

Middle Eastern (MID) AF: 0.0145 AC: 77 AN: 5322

European-Non Finnish (NFE) AF: 0.000569 AC: 528 AN: 927712

Other (OTH) AF: 0.00960 AC: 513 AN: 53448

GnomAD4 genome AF: 0.0364 AC: 5537 AN: 152232 Hom.: 339 Cov.: 32 AF XY: 0.0352 AC XY: 2617 AN XY: 74444

African (AFR) AF: 0.124 AC: 5133 AN: 41514

American (AMR) AF: 0.0178 AC: 272 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68002

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0298 Hom.: 29

Bravo AF: 0.0415

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.4
DANN	Benign	0.67
PhyloP100		-0.88
PromoterAI		-0.023	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs115471631; hg19: chr16-67199359;