chr13-31138848-T-C

Variant names:

• chr13-31138848-T-C
• NM_006644.4:c.2141A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006644.4(HSPH1):​c.2141A>G​(p.Lys714Arg) 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 benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPH1 NM_006644.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.147
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04474005).

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.2141A>G	p.Lys714Arg	missense	Exon 16 of 18	NP_006635.2
	HSPH1	NM_001286504.1		c.2147A>G	p.Lys716Arg	missense	Exon 16 of 18	NP_001273433.1	Q92598-4
	HSPH1	NM_001349704.2		c.2141A>G	p.Lys714Arg	missense	Exon 16 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.2141A>G	p.Lys714Arg	missense	Exon 16 of 18	ENSP00000318687.5	Q92598-1
	HSPH1	ENST00000630972.2	TSL:1	c.2147A>G	p.Lys716Arg	missense	Exon 16 of 18	ENSP00000487365.1	Q92598-4
	HSPH1	ENST00000380405.7	TSL:1	c.2009A>G	p.Lys670Arg	missense	Exon 15 of 17	ENSP00000369768.4	Q92598-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	0.063
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.71	N
PhyloP100		-0.15
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.059
Sift	Benign	0.35	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.090
MutPred		0.24		Loss of ubiquitination at K714 (P = 0.0087)
MVP		0.28
MPC		0.33
ClinPred		0.093	T
GERP RS		-2.4
PromoterAI		0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.026
gMVP		0.14
Mutation Taster		=95/5	polymorphism

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

hg19: chr13-31712985;