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.

Transcripts

RefSeq

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

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 v4.3

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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13-31148483-TAAAAAAA-TAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over