13-31148483-TAAAAAAA-TAAAA

Variant names:

• chr13-31148483-TAAA-T
• rs35594388
• NM_006644.4:c.1138-6_1138-4delTTT

Variant summary

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

The NM_006644.4(HSPH1):​c.1138-6_1138-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00918 in 973,754 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000050 (0 hom., cov: 0)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: HSPH1 NM_006644.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.797
• 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.1138-6_1138-4delTTT		splice_region intron	N/A	NP_006635.2
	HSPH1	NM_001286504.1		c.1144-6_1144-4delTTT		splice_region intron	N/A	NP_001273433.1	Q92598-4
	HSPH1	NM_001349704.2		c.1138-6_1138-4delTTT		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.1138-6_1138-4delTTT		splice_region intron	N/A	ENSP00000318687.5	Q92598-1
	HSPH1	ENST00000630972.2	TSL:1	c.1144-6_1144-4delTTT		splice_region intron	N/A	ENSP00000487365.1	Q92598-4
	HSPH1	ENST00000380405.7	TSL:1	c.1138-6_1138-4delTTT		splice_region intron	N/A	ENSP00000369768.4	Q92598-2

Frequencies

GnomAD3 genomes AF: 0.0000504 AC: 6 AN: 118980 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000918

Gnomad ASJ AF: 0.000328

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000336

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00457 AC: 498 AN: 108980 AF XY: 0.00496

Gnomad AFR exome AF: 0.00164

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00154

Gnomad FIN exome AF: 0.00435

Gnomad NFE exome AF: 0.00503

Gnomad OTH exome AF: 0.00305

GnomAD4 exome AF: 0.0104 AC: 8930 AN: 854774 Hom.: 0 AF XY: 0.0106 AC XY: 4540 AN XY: 429212

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

African (AFR) AF: 0.00585 AC: 108 AN: 18458

American (AMR) AF: 0.00565 AC: 104 AN: 18402

Ashkenazi Jewish (ASJ) AF: 0.00928 AC: 138 AN: 14874

East Asian (EAS) AF: 0.00180 AC: 53 AN: 29462

South Asian (SAS) AF: 0.00875 AC: 339 AN: 38724

European-Finnish (FIN) AF: 0.00865 AC: 309 AN: 35716

Middle Eastern (MID) AF: 0.00710 AC: 29 AN: 4082

European-Non Finnish (NFE) AF: 0.0113 AC: 7452 AN: 658134

Other (OTH) AF: 0.0108 AC: 398 AN: 36922

⚠️ 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: 0.0000504 AC: 6 AN: 118980 Hom.: 0 Cov.: 0 AF XY: 0.0000534 AC XY: 3 AN XY: 56184

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

African (AFR) AF: 0.0000324 AC: 1 AN: 30828

American (AMR) AF: 0.0000918 AC: 1 AN: 10894

Ashkenazi Jewish (ASJ) AF: 0.000328 AC: 1 AN: 3048

East Asian (EAS) AF: 0.00 AC: 0 AN: 3330

South Asian (SAS) AF: 0.00 AC: 0 AN: 3344

European-Finnish (FIN) AF: 0.000188 AC: 1 AN: 5312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.0000336 AC: 2 AN: 59590

Other (OTH) AF: 0.00 AC: 0 AN: 1576

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000190724), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.80
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;