13-31148483-TAAAAAAA-TAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

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. 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 0.0014 (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

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

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

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

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

GnomAD3 exomes AF: 0.254 AC: 27632 AN: 108980 Hom.: 0 AF XY: 0.264 AC XY: 15863 AN XY: 60134

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 SAS exome AF: 0.175

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

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.149

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.0479

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.146

Gnomad4 OTH exome AF: 0.134

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

Gnomad4 AFR AF: 0.000389

Gnomad4 AMR AF: 0.000918

Gnomad4 ASJ AF: 0.00131

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00660

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.00189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs35594388; hg19: chr13-31722620;