rs146520007

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_006644.4(HSPH1):c.754T>C(p.Tyr252His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000653 in 1,613,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 1 hom. )

Consequence

HSPH1
NM_006644.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.95

Publications

5 publications found

Variant links:

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]

HSPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33889192).

BS2

High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPH1	NM_006644.4 link	c.754T>C	p.Tyr252His	missense_variant	Exon 7 of 18	ENST00000320027.10	NP_006635.2	Q92598-1A0A024RDS1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSPH1	ENST00000320027.10 link	c.754T>C	p.Tyr252His	missense_variant	Exon 7 of 18	1	NM_006644.4	ENSP00000318687.5	Q92598-1
HSPH1	ENST00000602786.5 link	n.*282T>C		non_coding_transcript_exon_variant	Exon 6 of 17	1		ENSP00000473512.1	R4GN69
HSPH1	ENST00000602786.5 link	n.*282T>C		3_prime_UTR_variant	Exon 6 of 17	1		ENSP00000473512.1	R4GN69

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000382

AC:

AN:

251032

AF XY:

0.000376

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000696

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000682

AC:

996

AN:

1461400

Hom.:

Cov.:

AF XY:

0.000649

AC XY:

472

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33458

American (AMR)

AF:

0.000313

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000844

AC:

938

AN:

1111746

Other (OTH)

AF:

0.000497

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

105

158

210

263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000381

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41458

American (AMR)

AF:

0.000786

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68028

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000608

Hom.:

Bravo

AF:

0.000468

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Tyr252His variant in HSPH1 has not been previously associated with disease , but has been identified in 0.1% (35/66586) of European chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14652000 7). Computational prediction tools and conservation analysis suggest that the p. Tyr252His variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, the clinical significance of the p.Tyr252His variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Benign

0.081

MetaRNN

Benign

0.34

T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.95

.;L;.;L

PhyloP100

8.9

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.7

.;D;.;D

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

.;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;.;D

Vest4

0.70

MVP

0.66

MPC

1.4

ClinPred

0.36

GERP RS

5.7

Varity_R

0.91

gMVP

0.48

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over