NM_006644.4:c.2342G>A

Variant names:

• chr13-31138435-C-T
• rs73171026
• NM_006644.4:c.2342G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006644.4(HSPH1):​c.2342G>A​(p.Arg781His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,613,016 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (22 hom.)
• Consequence: HSPH1 NM_006644.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.713
• Publications: 8 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044371784).
• BP6: Variant 13-31138435-C-T is Benign according to our data. Variant chr13-31138435-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 782784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 509 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPH1	NM_006644.4	MANE Select	c.2342G>A	p.Arg781His	missense	Exon 17 of 18	NP_006635.2
	HSPH1	NM_001286504.1		c.2348G>A	p.Arg783His	missense	Exon 17 of 18	NP_001273433.1	Q92598-4
	HSPH1	NM_001349704.2		c.2342G>A	p.Arg781His	missense	Exon 17 of 19	NP_001336633.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPH1	ENST00000320027.10	TSL:1 MANE Select	c.2342G>A	p.Arg781His	missense	Exon 17 of 18	ENSP00000318687.5	Q92598-1
	HSPH1	ENST00000630972.2	TSL:1	c.2348G>A	p.Arg783His	missense	Exon 17 of 18	ENSP00000487365.1	Q92598-4
	HSPH1	ENST00000380405.7	TSL:1	c.2210G>A	p.Arg737His	missense	Exon 16 of 17	ENSP00000369768.4	Q92598-2

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 509 AN: 152064 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00444

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00326 AC: 817 AN: 250742 AF XY: 0.00316

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00606

GnomAD4 exome AF: 0.00420 AC: 6137 AN: 1460834 Hom.: 22 Cov.: 31 AF XY: 0.00412 AC XY: 2992 AN XY: 726734

African (AFR) AF: 0.000509 AC: 17 AN: 33418

American (AMR) AF: 0.00359 AC: 160 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 424 AN: 26102

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39670

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86172

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00469 AC: 5215 AN: 1111370

Other (OTH) AF: 0.00429 AC: 259 AN: 60344

GnomAD4 genome AF: 0.00334 AC: 509 AN: 152182 Hom.: 2 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74416

African (AFR) AF: 0.00128 AC: 53 AN: 41544

American (AMR) AF: 0.00556 AC: 85 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00444 AC: 302 AN: 67952

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00434 Hom.: 1

Bravo AF: 0.00368

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00298 AC: 362

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.71
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.037
Sift	Benign	0.17	T
Sift4G	Benign	0.54	T
Polyphen		0.90	P
Vest4		0.14
MVP		0.54
MPC		0.50
ClinPred		0.0044	T
GERP RS		2.4
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.34
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: rs73171026; hg19: chr13-31712572; COSMIC: COSV104410526; COSMIC: COSV104410526;