6-31810522-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005527.4(HSPA1L):c.1451C>T(p.Ala484Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HSPA1L NM_005527.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.10

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA1L	NM_005527.4	c.1451C>T	p.Ala484Val	missense_variant	2/2	ENST00000375654.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPA1L	ENST00000375654.5	c.1451C>T	p.Ala484Val	missense_variant	2/2	1	NM_005527.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460822 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 726664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.1451C>T (p.A484V) alteration is located in exon 2 (coding exon 1) of the HSPA1L gene. This alteration results from a C to T substitution at nucleotide position 1451, causing the alanine (A) at amino acid position 484 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.082	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.047	D
Polyphen		0.99	D
Vest4		0.83
MutPred		0.78		Loss of catalytic residue at A484 (P = 0.0474);
MVP		0.84
MPC		0.94
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.28
gMVP		0.22

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: rs548364201; hg19: chr6-31778299;