chr14-64542203-A-T
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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
NM_021979.4 missense
Scores
2
4
13
Clinical Significance
Conservation
PhyloP100: 9.32
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]
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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 |
---|---|---|---|---|---|---|---|---|
HSPA2 | NM_021979.4 | c.1354A>T | p.Met452Leu | missense_variant | 1/1 | ENST00000247207.7 | NP_068814.2 | |
HSPA2 | NM_001387931.1 | c.1354A>T | p.Met452Leu | missense_variant | 2/2 | NP_001374860.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HSPA2 | ENST00000247207.7 | c.1354A>T | p.Met452Leu | missense_variant | 1/1 | NM_021979.4 | ENSP00000247207 | P1 | ||
HSPA2 | ENST00000394709.2 | c.1354A>T | p.Met452Leu | missense_variant | 2/2 | 1 | ENSP00000378199 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151978Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251364Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135900
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461760Hom.: 0 Cov.: 86 AF XY: 0.00 AC XY: 0AN XY: 727190
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151978Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74186
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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 submitter | clinical testing | Ambry Genetics | Feb 05, 2024 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
Gain of catalytic residue at K454 (P = 0.0914);Gain of catalytic residue at K454 (P = 0.0914);
MVP
ClinPred
D
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at