17-58480256-C-T

Variant names:

• chr17-58480256-C-T
• rs117884653
• NM_001080439.3:c.562G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001080439.3(HSF5):​c.562G>A​(p.Val188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000301 in 1,609,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: HSF5 NM_001080439.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.709

Genes affected

HSF5 (HGNC:26862): (heat shock transcription factor 5) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038462907).
• BS2: High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSF5	NM_001080439.3	c.562G>A	p.Val188Ile	missense_variant	Exon 2 of 6	ENST00000323777.8	NP_001073908.2
HSF5	XM_011524283.2	c.562G>A	p.Val188Ile	missense_variant	Exon 2 of 6		XP_011522585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSF5	ENST00000323777.8	c.562G>A	p.Val188Ile	missense_variant	Exon 2 of 6	1	NM_001080439.3	ENSP00000313243.3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000304 AC: 74 AN: 243360 Hom.: 0 AF XY: 0.000395 AC XY: 52 AN XY: 131786

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.0000881

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000739

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000306 AC: 446 AN: 1456778 Hom.: 0 Cov.: 32 AF XY: 0.000318 AC XY: 230 AN XY: 724214

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000451

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000689

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000306

Gnomad4 OTH exome AF: 0.000415

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74482

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000372 Hom.: 1

Bravo AF: 0.000223

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000330 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.562G>A (p.V188I) alteration is located in exon 2 (coding exon 2) of the HSF5 gene. This alteration results from a G to A substitution at nucleotide position 562, causing the valine (V) at amino acid position 188 to be replaced by an isoleucine (I). 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	Benign	0.093
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.18	T
Vest4		0.091
MVP		0.28
MPC		0.16
ClinPred		0.027	T
GERP RS		5.6
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117884653; hg19: chr17-56557617;