rs2227955

Positions:

• chr6-31810300-T-G

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.1673A>C​(p.Glu558Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0296 in 1,558,830 control chromosomes in the GnomAD database, including 927 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (187 hom., cov: 32)
  • Exomes 𝑓: 0.028 (740 hom.)
• Consequence: HSPA1L NM_005527.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 6.27

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=0.0021847188).
• BP6: Variant 6-31810300-T-G is Benign according to our data. Variant chr6-31810300-T-G is described in ClinVar as [Benign]. Clinvar id is 372131.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA1L	NM_005527.4	c.1673A>C	p.Glu558Ala	missense_variant	2/2	ENST00000375654.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPA1L	ENST00000375654.5	c.1673A>C	p.Glu558Ala	missense_variant	2/2	1	NM_005527.4	P1

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6315 AN: 152140 Hom.: 187 Cov.: 32

Gnomad AFR AF: 0.0830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0305

Gnomad ASJ AF: 0.0113

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0406

GnomAD3 exomes AF: 0.0318 AC: 6531 AN: 205372 Hom.: 166 AF XY: 0.0313 AC XY: 3448 AN XY: 110132

Gnomad AFR exome AF: 0.0847

Gnomad AMR exome AF: 0.0326

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.00951

Gnomad SAS exome AF: 0.0443

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.0283

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0284 AC: 39887 AN: 1406572 Hom.: 740 Cov.: 36 AF XY: 0.0289 AC XY: 20117 AN XY: 695544

Gnomad4 AFR exome AF: 0.0858

Gnomad4 AMR exome AF: 0.0318

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.0140

Gnomad4 SAS exome AF: 0.0436

Gnomad4 FIN exome AF: 0.0189

Gnomad4 NFE exome AF: 0.0267

Gnomad4 OTH exome AF: 0.0312

GnomAD4 genome AF: 0.0415 AC: 6316 AN: 152258 Hom.: 187 Cov.: 32 AF XY: 0.0412 AC XY: 3070 AN XY: 74446

Gnomad4 AFR AF: 0.0829

Gnomad4 AMR AF: 0.0304

Gnomad4 ASJ AF: 0.0113

Gnomad4 EAS AF: 0.0137

Gnomad4 SAS AF: 0.0400

Gnomad4 FIN AF: 0.0156

Gnomad4 NFE AF: 0.0271

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0295 Hom.: 155

Bravo AF: 0.0436

TwinsUK AF: 0.0280 AC: 104

ALSPAC AF: 0.0291 AC: 112

ESP6500AA AF: 0.0808 AC: 356

ESP6500EA AF: 0.0264 AC: 227

ExAC AF: 0.0330 AC: 4010

Asia WGS AF: 0.0350 AC: 125 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

This variant is associated with the following publications: (PMID: 28126021) -

HSPA1L-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 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). -

Inflammatory bowel disease 1 Other:1

association, no assertion criteria provided

research

Human Development and Health, University of Southampton

Aug 06, 2016

HSPA1L loss of function - Our results indicate that de novo and rare mutations in HSPA1L are associated with IBD and provide insights into the pathogenesis of IBD -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.054
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.21	T
Polyphen		0.30	B
Vest4		0.25
MPC		0.40
ClinPred		0.040	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.31

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: rs2227955; hg19: chr6-31778077; COSMIC: COSV65150525; COSMIC: COSV65150525;