rs121909050

Variant names:

• chr16-67165742-A-G
• rs121909050
• NM_001374675.1:c.256A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001374675.1(HSF4):​c.256A>G​(p.Ile86Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I86T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSF4 NM_001374675.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.62
• Publications: 8 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-67165742-A-G is Pathogenic according to our data. Variant chr16-67165742-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 7095.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30534673). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSF4	NM_001374675.1	c.256A>G	p.Ile86Val	missense_variant	Exon 3 of 13	ENST00000521374.6	NP_001361604.1
HSF4	NM_001040667.3	c.256A>G	p.Ile86Val	missense_variant	Exon 5 of 15		NP_001035757.1
HSF4	NM_001374674.1	c.256A>G	p.Ile86Val	missense_variant	Exon 3 of 13		NP_001361603.1
HSF4	NM_001538.4	c.256A>G	p.Ile86Val	missense_variant	Exon 5 of 15		NP_001529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSF4	ENST00000521374.6	c.256A>G	p.Ile86Val	missense_variant	Exon 3 of 13	1	NM_001374675.1	ENSP00000430947.2
ENSG00000265690	ENST00000580114.5	n.*785A>G		non_coding_transcript_exon_variant	Exon 5 of 5	5		ENSP00000464271.1
ENSG00000265690	ENST00000580114.5	n.*785A>G		3_prime_UTR_variant	Exon 5 of 5	5		ENSP00000464271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000764 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataract 5 multiple types Pathogenic:1

Jul 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.30	T;T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	-0.39	.;N;N;.
PhyloP100		3.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.49	N;N;.;N
REVEL	Uncertain	0.49
Sift	Benign	0.29	T;T;.;T
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.0, 0.0010	.;B;B;.
Vest4		0.50, 0.50
MutPred		0.66		Gain of disorder (P = 0.0635);Gain of disorder (P = 0.0635);Gain of disorder (P = 0.0635);.;
MVP		0.71
ClinPred		0.82	D
GERP RS		4.9
PromoterAI		-0.0081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.28
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121909050; hg19: chr16-67199645; COSMIC: COSV50458201; COSMIC: COSV50458201;