NM_001374675.1:c.185A>G

Variant names:

• chr16-67165583-A-G
• NM_001374675.1:c.185A>G

Variant summary

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

The NM_001374675.1(HSF4):​c.185A>G​(p.Tyr62Cys) variant causes a missense change. 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: 6.29

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]

ENSG00000265690 (HGNC:):

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, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSF4	NM_001374675.1	c.185A>G	p.Tyr62Cys	missense_variant	Exon 2 of 13	ENST00000521374.6	NP_001361604.1
HSF4	NM_001040667.3	c.185A>G	p.Tyr62Cys	missense_variant	Exon 4 of 15		NP_001035757.1
HSF4	NM_001374674.1	c.185A>G	p.Tyr62Cys	missense_variant	Exon 2 of 13		NP_001361603.1
HSF4	NM_001538.4	c.185A>G	p.Tyr62Cys	missense_variant	Exon 4 of 15		NP_001529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSF4	ENST00000521374.6	c.185A>G	p.Tyr62Cys	missense_variant	Exon 2 of 13	1	NM_001374675.1	ENSP00000430947.2
ENSG00000265690	ENST00000580114.5	n.*714A>G		non_coding_transcript_exon_variant	Exon 4 of 5	5		ENSP00000464271.1
ENSG00000265690	ENST00000580114.5	n.*714A>G		3_prime_UTR_variant	Exon 4 of 5	5		ENSP00000464271.1

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

Inborn genetic diseases Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.185A>G (p.Y62C) alteration is located in exon 4 (coding exon 2) of the HSF4 gene. This alteration results from a A to G substitution at nucleotide position 185, causing the tyrosine (Y) at amino acid position 62 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.4	.;M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.1	D;D;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.92, 0.81
MutPred		0.81		Gain of catalytic residue at S66 (P = 0.0568);Gain of catalytic residue at S66 (P = 0.0568);Gain of catalytic residue at S66 (P = 0.0568);.;
MVP		0.92
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-67199486;