13-31148483-TAAAAAAA-TA

Variant names:

• chr13-31148483-TAAAAAA-T
• rs35594388
• NM_006644.4:c.1138-9_1138-4delTTTTTT

Variant summary

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

The NM_006644.4(HSPH1):​c.1138-9_1138-4delTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000462 in 866,338 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: HSPH1 NM_006644.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.797
• Publications: 0 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 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPH1	NM_006644.4	MANE Select	c.1138-9_1138-4delTTTTTT		splice_region intron	N/A	NP_006635.2
	HSPH1	NM_001286504.1		c.1144-9_1144-4delTTTTTT		splice_region intron	N/A	NP_001273433.1	Q92598-4
	HSPH1	NM_001349704.2		c.1138-9_1138-4delTTTTTT		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.1138-9_1138-4delTTTTTT		splice_region intron	N/A	ENSP00000318687.5	Q92598-1
	HSPH1	ENST00000630972.2	TSL:1	c.1144-9_1144-4delTTTTTT		splice_region intron	N/A	ENSP00000487365.1	Q92598-4
	HSPH1	ENST00000380405.7	TSL:1	c.1138-9_1138-4delTTTTTT		splice_region intron	N/A	ENSP00000369768.4	Q92598-2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000462 AC: 4 AN: 866338 Hom.: 0 AF XY: 0.00000460 AC XY: 2 AN XY: 435024

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

African (AFR) AF: 0.00 AC: 0 AN: 18658

American (AMR) AF: 0.00 AC: 0 AN: 18506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15046

East Asian (EAS) AF: 0.00 AC: 0 AN: 29652

South Asian (SAS) AF: 0.00 AC: 0 AN: 39064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.00000599 AC: 4 AN: 667710

Other (OTH) AF: 0.00 AC: 0 AN: 37406

⚠️ 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 Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.80
Mutation Taster		=64/36	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35594388; hg19: chr13-31722620;