chr16-67165593-T-A

Position:

• chr16-67165593-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001374675.1(HSF4):​c.195T>A​(p.His65Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSF4 NM_001374675.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSF4	NM_001374675.1	c.195T>A	p.His65Gln	missense_variant	2/13	ENST00000521374.6
HSF4	NM_001040667.3	c.195T>A	p.His65Gln	missense_variant	4/15
HSF4	NM_001374674.1	c.195T>A	p.His65Gln	missense_variant	2/13
HSF4	NM_001538.4	c.195T>A	p.His65Gln	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSF4	ENST00000521374.6	c.195T>A	p.His65Gln	missense_variant	2/13	1	NM_001374675.1	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 5 multiple types Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. Missense variant, The variant locates in the DNA-binding domain which contains several pathogenic missense variants reported from congenital cataracts patients (PMID: 12089525). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 3CNET). Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;D;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.6	.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.9	D;D;.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.96, 0.87
MutPred		0.95		Gain of MoRF binding (P = 0.0992);Gain of MoRF binding (P = 0.0992);Gain of MoRF binding (P = 0.0992);.;
MVP		0.82
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.99
gMVP		0.77

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-67199496;