Genetic Variant HSPH1:c.1138-4dupT (chr13-31148483-T-TA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006644.4(HSPH1):c.1138-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0098 ( 0 hom. )

Consequence

HSPH1
NM_006644.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.36

Publications

2 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 -4 ACMG points.

BS2

High AC in GnomAd4 at 207 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPH1	NM_006644.4 link	c.1138-4dupT		splice_region_variant, intron_variant	Intron 8 of 17	ENST00000320027.10	NP_006635.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPH1	ENST00000320027.10 link	c.1138-4_1138-3insT		splice_region_variant, intron_variant	Intron 8 of 17	1	NM_006644.4	ENSP00000318687.5
HSPH1	ENST00000602786.5 link	n.666-4_666-3insT		splice_region_variant, intron_variant	Intron 7 of 16	1		ENSP00000473512.1

Frequencies

GnomAD3 genomes

AF:

0.00174

AC:

207

AN:

118990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00402

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000826

Gnomad ASJ

AF:

0.000328

Gnomad EAS

AF:

0.00390

Gnomad SAS

AF:

0.00299

Gnomad FIN

AF:

0.000940

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000738

Gnomad OTH

AF:

0.000635

GnomAD2 exomes

AF:

0.00289

AC:

315

AN:

108980

AF XY:

0.00279

show subpopulations

Gnomad AFR exome

AF:

0.00367

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00363

Gnomad EAS exome

AF:

0.00601

Gnomad FIN exome

AF:

0.00473

Gnomad NFE exome

AF:

0.00187

Gnomad OTH exome

AF:

0.00356

GnomAD4 exome

AF:

0.00977

AC:

8450

AN:

864572

Hom.:

Cov.:

AF XY:

0.00956

AC XY:

4152

AN XY:

434136

show subpopulations

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

African (AFR)

AF:

0.0137

AC:

255

AN:

18618

American (AMR)

AF:

0.00542

AC:

100

AN:

18460

Ashkenazi Jewish (ASJ)

AF:

0.00747

AC:

112

AN:

15002

East Asian (EAS)

AF:

0.0110

AC:

325

AN:

29614

South Asian (SAS)

AF:

0.0152

AC:

592

AN:

38988

European-Finnish (FIN)

AF:

0.00693

AC:

250

AN:

36094

Middle Eastern (MID)

AF:

0.00829

AC:

AN:

4102

European-Non Finnish (NFE)

AF:

0.00965

AC:

6431

AN:

666358

Other (OTH)

AF:

0.00940

AC:

351

AN:

37336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.296

Heterozygous variant carriers

786

1572

2359

3145

3931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

288

576

864

1152

1440

<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:

0.00174

AC:

207

AN:

118976

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

AN XY:

56202

show subpopulations

African (AFR)

AF:

0.00402

AC:

124

AN:

30856

American (AMR)

AF:

0.000826

AC:

AN:

10896

Ashkenazi Jewish (ASJ)

AF:

0.000328

AC:

AN:

3046

East Asian (EAS)

AF:

0.00391

AC:

AN:

3324

South Asian (SAS)

AF:

0.00300

AC:

AN:

3332

European-Finnish (FIN)

AF:

0.000940

AC:

AN:

5318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.000738

AC:

AN:

59584

Other (OTH)

AF:

0.000631

AC:

AN:

1584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000457

Hom.:

372

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-3.4

Mutation Taster

=98/2

polymorphism

(source)

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

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13-31148483-TAAAAAAA-TAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over