NM_006644.4:c.1138-4dupT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006644.4(HSPH1):​c.1138-4dupT 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0098 (0 hom.)
• Consequence: HSPH1 NM_006644.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.36
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 207 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPH1	NM_006644.4	MANE Select	c.1138-4dupT		splice_region intron	N/A	NP_006635.2
	HSPH1	NM_001286504.1		c.1144-4dupT		splice_region intron	N/A	NP_001273433.1
	HSPH1	NM_001349704.2		c.1138-4dupT		splice_region intron	N/A	NP_001336633.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPH1	ENST00000320027.10	TSL:1 MANE Select	c.1138-4_1138-3insT		splice_region intron	N/A	ENSP00000318687.5
	HSPH1	ENST00000630972.2	TSL:1	c.1144-4_1144-3insT		splice_region intron	N/A	ENSP00000487365.1
	HSPH1	ENST00000380405.7	TSL:1	c.1138-4_1138-3insT		splice_region intron	N/A	ENSP00000369768.4

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 207 AN: 118990 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00402

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000826

Gnomad ASJ AF: 0.000328

Gnomad EAS AF: 0.00390

Gnomad SAS AF: 0.00299

Gnomad FIN AF: 0.000940

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000738

Gnomad OTH AF: 0.000635

GnomAD2 exomes AF: 0.00289 AC: 315 AN: 108980 AF XY: 0.00279

Gnomad AFR exome AF: 0.00367

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00363

Gnomad EAS exome AF: 0.00601

Gnomad FIN exome AF: 0.00473

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.00356

GnomAD4 exome AF: 0.00977 AC: 8450 AN: 864572 Hom.: 0 Cov.: 0 AF XY: 0.00956 AC XY: 4152 AN XY: 434136

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

African (AFR) AF: 0.0137 AC: 255 AN: 18618

American (AMR) AF: 0.00542 AC: 100 AN: 18460

Ashkenazi Jewish (ASJ) AF: 0.00747 AC: 112 AN: 15002

East Asian (EAS) AF: 0.0110 AC: 325 AN: 29614

South Asian (SAS) AF: 0.0152 AC: 592 AN: 38988

European-Finnish (FIN) AF: 0.00693 AC: 250 AN: 36094

Middle Eastern (MID) AF: 0.00829 AC: 34 AN: 4102

European-Non Finnish (NFE) AF: 0.00965 AC: 6431 AN: 666358

Other (OTH) AF: 0.00940 AC: 351 AN: 37336

⚠️ 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: 0.00174 AC: 207 AN: 118976 Hom.: 0 Cov.: 0 AF XY: 0.00165 AC XY: 93 AN XY: 56202

African (AFR) AF: 0.00402 AC: 124 AN: 30856

American (AMR) AF: 0.000826 AC: 9 AN: 10896

Ashkenazi Jewish (ASJ) AF: 0.000328 AC: 1 AN: 3046

East Asian (EAS) AF: 0.00391 AC: 13 AN: 3324

South Asian (SAS) AF: 0.00300 AC: 10 AN: 3332

European-Finnish (FIN) AF: 0.000940 AC: 5 AN: 5318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 220

European-Non Finnish (NFE) AF: 0.000738 AC: 44 AN: 59584

Other (OTH) AF: 0.000631 AC: 1 AN: 1584

Alfa AF: 0.000457 Hom.: 372

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.4
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs35594388; hg19: chr13-31722620;