rs2075800

chr6-31810169-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005527.4(HSPA1L):c.1804G>A(p.Glu602Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,526,028 control chromosomes in the GnomAD database, including 78,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.26 (6366 hom., cov: 32)
  • Exomes 𝑓: 0.32 (72131 hom.)
• Consequence: HSPA1L NM_005527.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.91

Genes affected

HSPA1L (HGNC:5234): (heat shock protein family A (Hsp70) member 1 like) This gene encodes a 70kDa heat shock protein. In conjunction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which also encode isoforms of the 70kDa heat shock protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037553012).
• BP6: Variant 6-31810169-C-T is Benign according to our data. Variant chr6-31810169-C-T is described in ClinVar as [Benign]. Clinvar id is 3059263.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA1L	NM_005527.4	c.1804G>A	p.Glu602Lys	missense_variant	2/2	ENST00000375654.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPA1L	ENST00000375654.5	c.1804G>A	p.Glu602Lys	missense_variant	2/2	1	NM_005527.4	P1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38959 AN: 151994 Hom.: 6360 Cov.: 32

Gnomad AFR AF: 0.0582

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.277

GnomAD3 exomes AF: 0.322 AC: 57626 AN: 179186 Hom.: 10244 AF XY: 0.329 AC XY: 31032 AN XY: 94420

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.494

Gnomad EAS exome AF: 0.386

Gnomad SAS exome AF: 0.299

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.346

Gnomad OTH exome AF: 0.320

GnomAD4 exome AF: 0.317 AC: 436075 AN: 1373916 Hom.: 72131 Cov.: 36 AF XY: 0.320 AC XY: 216215 AN XY: 675512

Gnomad4 AFR exome AF: 0.0446

Gnomad4 AMR exome AF: 0.366

Gnomad4 ASJ exome AF: 0.498

Gnomad4 EAS exome AF: 0.446

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.293

Gnomad4 NFE exome AF: 0.318

Gnomad4 OTH exome AF: 0.303

GnomAD4 genome AF: 0.256 AC: 38974 AN: 152112 Hom.: 6366 Cov.: 32 AF XY: 0.258 AC XY: 19212 AN XY: 74336

Gnomad4 AFR AF: 0.0581

Gnomad4 AMR AF: 0.315

Gnomad4 ASJ AF: 0.512

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.296

Gnomad4 NFE AF: 0.328

Gnomad4 OTH AF: 0.277

Alfa AF: 0.329 Hom.: 14548

Bravo AF: 0.250

ESP6500AA AF: 0.0651 AC: 287

ESP6500EA AF: 0.329 AC: 2826

ExAC AF: 0.316 AC: 37728

Asia WGS AF: 0.309 AC: 1079 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HSPA1L-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	6.3e-8	P;P
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.026	D
Polyphen		0.96	D
Vest4		0.26
MPC		0.91
ClinPred		0.027	T
GERP RS		5.9
Varity_R		0.26
gMVP		0.58

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: rs2075800; hg19: chr6-31777946; COSMIC: COSV65149724; COSMIC: COSV65149724;