chr13-31138435-C-T

Position:

• chr13-31138435-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006644.4(HSPH1):​c.2342G>A​(p.Arg781His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,613,016 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (22 hom.)
• Consequence: HSPH1 NM_006644.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.713

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

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044371784).
• BP6: Variant 13-31138435-C-T is Benign according to our data. Variant chr13-31138435-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 782784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 509 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPH1	NM_006644.4	c.2342G>A	p.Arg781His	missense_variant	17/18	ENST00000320027.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPH1	ENST00000320027.10	c.2342G>A	p.Arg781His	missense_variant	17/18	1	NM_006644.4	P1

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 509 AN: 152064 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00444

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00326 AC: 817 AN: 250742 Hom.: 2 AF XY: 0.00316 AC XY: 428 AN XY: 135564

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00606

GnomAD4 exome AF: 0.00420 AC: 6137 AN: 1460834 Hom.: 22 Cov.: 31 AF XY: 0.00412 AC XY: 2992 AN XY: 726734

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.00359

Gnomad4 ASJ exome AF: 0.0162

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00469

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.00334 AC: 509 AN: 152182 Hom.: 2 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74416

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00444

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00448 Hom.: 1

Bravo AF: 0.00368

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00298 AC: 362

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00421

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	HSPH1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.022	T;T;.;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0044	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	.;N;N;.;N
REVEL	Benign	0.037
Sift	Benign	0.17	.;T;T;.;T
Sift4G	Benign	0.54	T;T;D;T;T
Polyphen		0.90, 0.016	.;P;.;.;B
Vest4		0.14
MVP		0.54
MPC		0.50
ClinPred		0.0044	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs73171026; hg19: chr13-31712572; COSMIC: COSV104410526; COSMIC: COSV104410526;