13-31147971-C-T

Variant names:

• chr13-31147971-C-T
• rs1956328375
• NM_006644.4:c.1366G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006644.4(HSPH1):​c.1366G>A​(p.Glu456Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,433,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HSPH1 NM_006644.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86
• Publications: 0 publications found

Genes affected

HSPH1 (HGNC:16969): (heat shock protein family H (Hsp110) member 1) This gene encodes a member of the heat shock protein 70 family of proteins. The encoded protein functions as a nucleotide exchange factor for the molecular chaperone heat shock cognate 71 kDa protein (Hsc70). In addition, this protein plays a distinct but related role as a holdase that inhibits the aggregation of misfolded proteins, including the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Elevated expression of this protein has been observed in numerous human cancers. [provided by RefSeq, Mar 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006644.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPH1	NM_006644.4	MANE Select	c.1366G>A	p.Glu456Lys	missense	Exon 10 of 18	NP_006635.2
	HSPH1	NM_001286504.1		c.1372G>A	p.Glu458Lys	missense	Exon 10 of 18	NP_001273433.1	Q92598-4
	HSPH1	NM_001349704.2		c.1366G>A	p.Glu456Lys	missense	Exon 10 of 19	NP_001336633.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPH1	ENST00000320027.10	TSL:1 MANE Select	c.1366G>A	p.Glu456Lys	missense	Exon 10 of 18	ENSP00000318687.5	Q92598-1
	HSPH1	ENST00000630972.2	TSL:1	c.1372G>A	p.Glu458Lys	missense	Exon 10 of 18	ENSP00000487365.1	Q92598-4
	HSPH1	ENST00000380405.7	TSL:1	c.1366G>A	p.Glu456Lys	missense	Exon 10 of 17	ENSP00000369768.4	Q92598-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1433762 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712928

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31214

American (AMR) AF: 0.00 AC: 0 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24810

East Asian (EAS) AF: 0.00 AC: 0 AN: 39380

South Asian (SAS) AF: 0.00 AC: 0 AN: 80326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1104404

Other (OTH) AF: 0.00 AC: 0 AN: 59122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0965794), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.28
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.029	D
Polyphen		0.099	B
Vest4		0.72
MutPred		0.65		Gain of methylation at E456 (P = 0.0071)
MVP		0.84
MPC		0.91
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.48
gMVP		0.63
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs1956328375; hg19: chr13-31722108;