rs121909048

chr16-67165827-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001374675.1(HSF4):c.341T>C(p.Leu114Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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. L114Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSF4 NM_001374675.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001374675.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-67165827-T-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 16-67165827-T-C is Pathogenic according to our data. Variant chr16-67165827-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 7092.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-67165827-T-C is described in Lovd as [Pathogenic]. Variant chr16-67165827-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSF4	NM_001374675.1	c.341T>C	p.Leu114Pro	missense_variant	3/13	ENST00000521374.6
HSF4	NM_001040667.3	c.341T>C	p.Leu114Pro	missense_variant	5/15
HSF4	NM_001374674.1	c.341T>C	p.Leu114Pro	missense_variant	3/13
HSF4	NM_001538.4	c.341T>C	p.Leu114Pro	missense_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSF4	ENST00000521374.6	c.341T>C	p.Leu114Pro	missense_variant	3/13	1	NM_001374675.1	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataract 5 multiple types Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.6	D;D;.;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0080	D;D;.;D
Sift4G	Uncertain	0.026	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.99, 0.90
MutPred		0.94		Loss of stability (P = 0.0674);Loss of stability (P = 0.0674);Loss of stability (P = 0.0674);.;
MVP		0.92
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909048; hg19: chr16-67199730;