13-31148034-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006644.4(HSPH1):c.1303C>G(p.Leu435Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000916 in 1,610,768 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (7 hom., cov: 31)
  • Exomes 𝑓: 0.00075 (15 hom.)
• Consequence: HSPH1 NM_006644.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.474

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010216743).
• BP6: Variant 13-31148034-G-C is Benign according to our data. Variant chr13-31148034-G-C is described in ClinVar as [Benign]. Clinvar id is 769845.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0025 (381/152152) while in subpopulation AMR AF= 0.024 (366/15262). AF 95% confidence interval is 0.022. There are 7 homozygotes in gnomad4. There are 232 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 378 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPH1	NM_006644.4	c.1303C>G	p.Leu435Val	missense_variant	10/18	ENST00000320027.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPH1	ENST00000320027.10	c.1303C>G	p.Leu435Val	missense_variant	10/18	1	NM_006644.4	P1

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 378 AN: 152034 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0238

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00332 AC: 824 AN: 248534 Hom.: 12 AF XY: 0.00255 AC XY: 343 AN XY: 134412

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.000750 AC: 1094 AN: 1458616 Hom.: 15 Cov.: 31 AF XY: 0.000660 AC XY: 479 AN XY: 725678

Gnomad4 AFR exome AF: 0.0000904

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.000929

GnomAD4 genome AF: 0.00250 AC: 381 AN: 152152 Hom.: 7 Cov.: 31 AF XY: 0.00312 AC XY: 232 AN XY: 74398

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.0240

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000309 Hom.: 0

Bravo AF: 0.00403

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00245 AC: 297

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 25, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0030	T;T;.;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.87	N;N;N;N;N
PrimateAI	Benign	0.47	T
REVEL	Benign	0.044
Sift4G	Benign	0.076	T;T;T;T
Polyphen		0.018, 0.0040	.;B;.;B
Vest4		0.30
MVP		0.25
MPC		0.45
ClinPred		0.013	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.25

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: rs181708109; hg19: chr13-31722171;