dbSNP rs35594388: HSPH1:c.1138-10_1138-4delTTTTTTT (chr13-31148483-TAAAAAAA-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006644.4(HSPH1):c.1138-10_1138-4delTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 866,362 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

HSPH1
NM_006644.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.797

Publications

0 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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	UniProt
HSPH1	NM_006644.4	MANE Select	c.1138-10_1138-4delTTTTTTT	splice_region intron	N/A	NP_006635.2
HSPH1	NM_001286504.1		c.1144-10_1144-4delTTTTTTT	splice_region intron	N/A	NP_001273433.1	Q92598-4
HSPH1	NM_001349704.2		c.1138-10_1138-4delTTTTTTT	splice_region intron	N/A	NP_001336633.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HSPH1	ENST00000320027.10	TSL:1 MANE Select	c.1138-10_1138-4delTTTTTTT	splice_region intron	N/A	ENSP00000318687.5	Q92598-1
HSPH1	ENST00000630972.2	TSL:1	c.1144-10_1144-4delTTTTTTT	splice_region intron	N/A	ENSP00000487365.1	Q92598-4
HSPH1	ENST00000380405.7	TSL:1	c.1138-10_1138-4delTTTTTTT	splice_region intron	N/A	ENSP00000369768.4	Q92598-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000346

AC:

AN:

866362

Hom.:

AF XY:

0.00000460

AC XY:

AN XY:

435038

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

18658

American (AMR)

AF:

0.00

AC:

AN:

18506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15046

East Asian (EAS)

AF:

0.00

AC:

AN:

29652

South Asian (SAS)

AF:

0.0000512

AC:

AN:

39066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.00000150

AC:

AN:

667730

Other (OTH)

AF:

0.00

AC:

AN:

37408

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.80

Splicing

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