Genetic Variant HSPH1:c.1138-7_1138-4delTTTT (chr13-31148483-TAAAA-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_006644.4(HSPH1):c.1138-7_1138-4delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000791 in 864,602 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00079 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HSPH1
NM_006644.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.797

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HSPH1	NM_006644.4	MANE Select	c.1138-7_1138-4delTTTT	splice_region intron	N/A	NP_006635.2
HSPH1	NM_001286504.1		c.1144-7_1144-4delTTTT	splice_region intron	N/A	NP_001273433.1
HSPH1	NM_001349704.2		c.1138-7_1138-4delTTTT	splice_region intron	N/A	NP_001336633.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HSPH1	ENST00000320027.10	TSL:1 MANE Select	c.1138-7_1138-4delTTTT	splice_region intron	N/A	ENSP00000318687.5
HSPH1	ENST00000630972.2	TSL:1	c.1144-7_1144-4delTTTT	splice_region intron	N/A	ENSP00000487365.1
HSPH1	ENST00000380405.7	TSL:1	c.1138-7_1138-4delTTTT	splice_region intron	N/A	ENSP00000369768.4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

118996

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000275

AC:

AN:

108980

AF XY:

0.000266

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000419

Gnomad ASJ exome

AF:

0.000363

Gnomad EAS exome

AF:

0.000140

Gnomad FIN exome

AF:

0.000378

Gnomad NFE exome

AF:

0.000219

Gnomad OTH exome

AF:

0.00102

GnomAD4 exome

AF:

0.000791

AC:

684

AN:

864602

Hom.:

AF XY:

0.000790

AC XY:

343

AN XY:

434118

show subpopulations

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

African (AFR)

AF:

0.000429

AC:

AN:

18640

American (AMR)

AF:

0.000595

AC:

AN:

18480

Ashkenazi Jewish (ASJ)

AF:

0.000733

AC:

AN:

15014

East Asian (EAS)

AF:

0.000101

AC:

AN:

29634

South Asian (SAS)

AF:

0.000923

AC:

AN:

38998

European-Finnish (FIN)

AF:

0.000526

AC:

AN:

36124

Middle Eastern (MID)

AF:

0.000487

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.000850

AC:

566

AN:

666264

Other (OTH)

AF:

0.000750

AC:

AN:

37340

⚠️ 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: 0.253

Heterozygous variant carriers

173

259

346

432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

118996

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

56194

African (AFR)

AF:

0.00

AC:

AN:

30828

American (AMR)

AF:

0.00

AC:

AN:

10898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3046

East Asian (EAS)

AF:

0.00

AC:

AN:

3330

South Asian (SAS)

AF:

0.00

AC:

AN:

3344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

59598

Other (OTH)

AF:

0.00

AC:

AN:

1576

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over