13-31148483-TAAAAAAA-TAAAAAA

Variant names:

• chr13-31148483-TA-T
• rs35594388
• NM_006644.4:c.1138-4delT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_006644.4(HSPH1):​c.1138-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.42 (9623 hom., cov: 0)
  • Exomes 𝑓: 0.42 (3817 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPH1 NM_006644.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.36

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 -10 ACMG points.

• BP6: Variant 13-31148483-TA-T is Benign according to our data. Variant chr13-31148483-TA-T is described in ClinVar as [Benign]. Clinvar id is 402951.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-31148483-TA-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.416 AC: 49446 AN: 118872 Hom.: 9629 Cov.: 0

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.683

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.402

GnomAD3 exomes AF: 0.463 AC: 50425 AN: 108980 Hom.: 81 AF XY: 0.461 AC XY: 27720 AN XY: 60134

Gnomad AFR exome AF: 0.464

Gnomad AMR exome AF: 0.459

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.448

Gnomad SAS exome AF: 0.440

Gnomad FIN exome AF: 0.468

Gnomad NFE exome AF: 0.468

Gnomad OTH exome AF: 0.470

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.423 AC: 361769 AN: 855930 Hom.: 3817 Cov.: 0 AF XY: 0.423 AC XY: 181729 AN XY: 429722

Gnomad4 AFR exome AF: 0.399

Gnomad4 AMR exome AF: 0.427

Gnomad4 ASJ exome AF: 0.421

Gnomad4 EAS exome AF: 0.410

Gnomad4 SAS exome AF: 0.376

Gnomad4 FIN exome AF: 0.433

Gnomad4 NFE exome AF: 0.426

Gnomad4 OTH exome AF: 0.420

GnomAD4 genome AF: 0.416 AC: 49428 AN: 118860 Hom.: 9623 Cov.: 0 AF XY: 0.411 AC XY: 23075 AN XY: 56156

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.0241

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.467

Gnomad4 NFE AF: 0.499

Gnomad4 OTH AF: 0.401

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;