14-64542203-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021979.4(HSPA2):​c.1354A>T​(p.Met452Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HSPA2
NM_021979.4 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32
Variant links:
Genes affected
HSPA2 (HGNC:5235): (heat shock protein family A (Hsp70) member 2) Enables disordered domain specific binding activity; enzyme binding activity; and unfolded protein binding activity. Involved in negative regulation of inclusion body assembly and protein refolding. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32441813).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HSPA2NM_021979.4 linkuse as main transcriptc.1354A>T p.Met452Leu missense_variant 1/1 ENST00000247207.7 NP_068814.2
HSPA2NM_001387931.1 linkuse as main transcriptc.1354A>T p.Met452Leu missense_variant 2/2 NP_001374860.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HSPA2ENST00000247207.7 linkuse as main transcriptc.1354A>T p.Met452Leu missense_variant 1/1 NM_021979.4 ENSP00000247207 P1
HSPA2ENST00000394709.2 linkuse as main transcriptc.1354A>T p.Met452Leu missense_variant 2/21 ENSP00000378199 P1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151978
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000389
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251364
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461760
Hom.:
0
Cov.:
86
AF XY:
0.00
AC XY:
0
AN XY:
727190
show subpopulations
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151978
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74186
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000389
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 05, 2024The c.1354A>T (p.M452L) alteration is located in exon 1 (coding exon 1) of the HSPA2 gene. This alteration results from a A to T substitution at nucleotide position 1354, causing the methionine (M) at amino acid position 452 to be replaced by a leucine (L). 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
0.14
BayesDel_addAF
Benign
-0.071
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
24
DANN
Benign
0.95
DEOGEN2
Benign
0.11
T;T
Eigen
Benign
0.12
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.88
.;D
M_CAP
Benign
0.0096
T
MetaRNN
Benign
0.32
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.42
N;N
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-1.7
N;N
REVEL
Uncertain
0.34
Sift
Uncertain
0.019
D;D
Sift4G
Benign
0.18
T;T
Polyphen
0.026
B;B
Vest4
0.66
MutPred
0.72
Gain of catalytic residue at K454 (P = 0.0914);Gain of catalytic residue at K454 (P = 0.0914);
MVP
0.31
ClinPred
0.62
D
GERP RS
5.3
Varity_R
0.51
gMVP
0.56

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs766204605; hg19: chr14-65008921; API