13-31148483-TAAAAAAA-TAAAAAAAAAA

Variant names:

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

Variant summary

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

The NM_006644.4(HSPH1):​c.1138-6_1138-4dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: HSPH1 NM_006644.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.36
• 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPH1	NM_006644.4	c.1138-6_1138-4dupTTT		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.1138-4_1138-3insTTT		splice_region_variant, intron_variant	Intron 8 of 17	1	NM_006644.4	ENSP00000318687.5
HSPH1	ENST00000602786.5	n.*666-4_*666-3insTTT		splice_region_variant, intron_variant	Intron 7 of 16	1		ENSP00000473512.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000231 AC: 20 AN: 866344 Hom.: 0 Cov.: 0 AF XY: 0.0000184 AC XY: 8 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: 18656

American (AMR) AF: 0.0000540 AC: 1 AN: 18506

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

East Asian (EAS) AF: 0.0000337 AC: 1 AN: 29652

South Asian (SAS) AF: 0.0000512 AC: 2 AN: 39062

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4106

European-Non Finnish (NFE) AF: 0.0000225 AC: 15 AN: 667720

Other (OTH) AF: 0.0000267 AC: 1 AN: 37408

⚠️ 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 v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.4
Mutation Taster		=99/1	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;