rs2227956

chr6-31810495-G-Achr6-31810495-G-Cchr6-31810495-G-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.1478C>T(p.Thr493Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.836 in 1,613,352 control chromosomes in the GnomAD database, including 566,847 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T493K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.88 (58821 hom., cov: 31)
  • Exomes 𝑓: 0.83 (508026 hom.)
• Consequence: HSPA1L NM_005527.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.346

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=6.9402125E-7).
• BP6: Variant 6-31810495-G-A is Benign according to our data. Variant chr6-31810495-G-A is described in ClinVar as [Benign]. Clinvar id is 3060421.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA1L	NM_005527.4	c.1478C>T	p.Thr493Met	missense_variant	2/2	ENST00000375654.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPA1L	ENST00000375654.5	c.1478C>T	p.Thr493Met	missense_variant	2/2	1	NM_005527.4	P1

Frequencies

GnomAD3 genomes AF: 0.877 AC: 133293 AN: 152002 Hom.: 58760 Cov.: 31

Gnomad AFR AF: 0.967

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.935

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.845

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.822

Gnomad OTH AF: 0.903

GnomAD3 exomes AF: 0.866 AC: 217175 AN: 250884 Hom.: 94552 AF XY: 0.864 AC XY: 117222 AN XY: 135624

Gnomad AFR exome AF: 0.969

Gnomad AMR exome AF: 0.940

Gnomad ASJ exome AF: 0.938

Gnomad EAS exome AF: 0.813

Gnomad SAS exome AF: 0.891

Gnomad FIN exome AF: 0.837

Gnomad NFE exome AF: 0.829

Gnomad OTH exome AF: 0.867

GnomAD4 exome AF: 0.832 AC: 1216116 AN: 1461232 Hom.: 508026 Cov.: 62 AF XY: 0.835 AC XY: 606890 AN XY: 726950

Gnomad4 AFR exome AF: 0.968

Gnomad4 AMR exome AF: 0.935

Gnomad4 ASJ exome AF: 0.934

Gnomad4 EAS exome AF: 0.875

Gnomad4 SAS exome AF: 0.890

Gnomad4 FIN exome AF: 0.833

Gnomad4 NFE exome AF: 0.815

Gnomad4 OTH exome AF: 0.843

GnomAD4 genome AF: 0.877 AC: 133414 AN: 152120 Hom.: 58821 Cov.: 31 AF XY: 0.878 AC XY: 65247 AN XY: 74346

Gnomad4 AFR AF: 0.966

Gnomad4 AMR AF: 0.912

Gnomad4 ASJ AF: 0.935

Gnomad4 EAS AF: 0.805

Gnomad4 SAS AF: 0.888

Gnomad4 FIN AF: 0.845

Gnomad4 NFE AF: 0.822

Gnomad4 OTH AF: 0.903

Alfa AF: 0.844 Hom.: 114932

Bravo AF: 0.886

TwinsUK AF: 0.820 AC: 3040

ALSPAC AF: 0.813 AC: 3135

ESP6500AA AF: 0.962 AC: 4237

ESP6500EA AF: 0.823 AC: 7079

ExAC AF: 0.865 AC: 105038

Asia WGS AF: 0.897 AC: 3122 AN: 3478

EpiCase AF: 0.837

EpiControl AF: 0.849

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 21, 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	Benign	0.064
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	8.0
Dann	Benign	0.92
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.25	N
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.93	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.078
Sift	Benign	0.097	T
Sift4G	Benign	0.098	T
Polyphen		0.13	B
Vest4		0.035
MPC		0.29
ClinPred		0.0068	T
GERP RS		-4.2
Varity_R		0.038
gMVP		0.14

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: rs2227956; hg19: chr6-31778272;