rs34620296

Positions:

• chr6-31811171-C-T

Variant summary

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

The NM_005527.4(HSPA1L):​c.802G>A​(p.Ala268Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,614,152 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (36 hom.)
• Consequence: HSPA1L NM_005527.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O: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=0.01235792).
• BP6: Variant 6-31811171-C-T is Benign according to our data. Variant chr6-31811171-C-T is described in ClinVar as [Benign]. Clinvar id is 372132.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00303 (4431/1461872) while in subpopulation SAS AF= 0.0229 (1973/86258). AF 95% confidence interval is 0.022. There are 36 homozygotes in gnomad4_exome. There are 2665 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 322 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA1L	NM_005527.4	c.802G>A	p.Ala268Thr	missense_variant	2/2	ENST00000375654.5	NP_005518.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPA1L	ENST00000375654.5	c.802G>A	p.Ala268Thr	missense_variant	2/2	1	NM_005527.4	ENSP00000364805.4

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00491 AC: 1233 AN: 251122 Hom.: 14 AF XY: 0.00603 AC XY: 819 AN XY: 135834

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.0239

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00303 AC: 4431 AN: 1461872 Hom.: 36 Cov.: 36 AF XY: 0.00366 AC XY: 2665 AN XY: 727238

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.00166

Gnomad4 SAS exome AF: 0.0229

Gnomad4 FIN exome AF: 0.00271

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.00432

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74454

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0179

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00191

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00198 Hom.: 0

Bravo AF: 0.00180

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00501 AC: 608

EpiCase AF: 0.00229

EpiControl AF: 0.00255

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

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

HSPA1L: BS1, BS2 -

HSPA1L-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2022

This variant is classified as likely 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	0.30
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.089	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.7	H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.80
MPC		0.93
ClinPred		0.10	T
GERP RS		5.3
Varity_R		0.38
gMVP		0.18

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: rs34620296; hg19: chr6-31778948;