13-31148483-TAAAAAAA-TAAAAA

Variant names:

• chr13-31148483-TAA-T
• rs35594388
• NM_006644.4:c.1138-5_1138-4delTT

Variant summary

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

The NM_006644.4(HSPH1):​c.1138-5_1138-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 963,100 control chromosomes in the GnomAD database, including 2 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.14 (2 hom.)
• Consequence: HSPH1 NM_006644.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.727
• Publications: 2 publications found

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]

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPH1	NM_006644.4	MANE Select	c.1138-5_1138-4delTT		splice_region intron	N/A	NP_006635.2
	HSPH1	NM_001286504.1		c.1144-5_1144-4delTT		splice_region intron	N/A	NP_001273433.1	Q92598-4
	HSPH1	NM_001349704.2		c.1138-5_1138-4delTT		splice_region intron	N/A	NP_001336633.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 165 AN: 118920 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000389

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00131

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00660

Gnomad MID AF: 0.00826

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00190

GnomAD2 exomes AF: 0.254 AC: 27632 AN: 108980 AF XY: 0.264

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.0934

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.308

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.140 AC: 118375 AN: 844196 Hom.: 2 AF XY: 0.143 AC XY: 60798 AN XY: 423788

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

African (AFR) AF: 0.104 AC: 1888 AN: 18088

American (AMR) AF: 0.149 AC: 2695 AN: 18086

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 1932 AN: 14582

East Asian (EAS) AF: 0.0479 AC: 1362 AN: 28426

South Asian (SAS) AF: 0.111 AC: 4236 AN: 38122

European-Finnish (FIN) AF: 0.158 AC: 5544 AN: 35180

Middle Eastern (MID) AF: 0.112 AC: 448 AN: 4000

European-Non Finnish (NFE) AF: 0.146 AC: 95383 AN: 651346

Other (OTH) AF: 0.134 AC: 4887 AN: 36366

⚠️ 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.

GnomAD4 genome AF: 0.00139 AC: 165 AN: 118904 Hom.: 0 Cov.: 0 AF XY: 0.00162 AC XY: 91 AN XY: 56176

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

African (AFR) AF: 0.000389 AC: 12 AN: 30850

American (AMR) AF: 0.000918 AC: 10 AN: 10892

Ashkenazi Jewish (ASJ) AF: 0.00131 AC: 4 AN: 3044

East Asian (EAS) AF: 0.00 AC: 0 AN: 3322

South Asian (SAS) AF: 0.00 AC: 0 AN: 3332

European-Finnish (FIN) AF: 0.00660 AC: 35 AN: 5300

Middle Eastern (MID) AF: 0.00909 AC: 2 AN: 220

European-Non Finnish (NFE) AF: 0.00166 AC: 99 AN: 59544

Other (OTH) AF: 0.00189 AC: 3 AN: 1584

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 372

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs35594388; hg19: chr13-31722620;