chr5-133064990-T-G

Variant summary

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

The NM_002154.4(HSPA4):​c.118T>G​(p.Ser40Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

HSPA4
NM_002154.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.22
Variant links:
Genes affected
HSPA4 (HGNC:5237): (heat shock protein family A (Hsp70) member 4) Predicted to enable ATP binding activity. Involved in chaperone-mediated protein complex assembly and protein insertion into mitochondrial outer membrane. Located in cytosol and extracellular exosome. Implicated in Chagas disease. Biomarker of chronic obstructive pulmonary disease; rheumatoid arthritis; type 2 diabetes mellitus; and ulcerative colitis. [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=0.34727204).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HSPA4NM_002154.4 linkc.118T>G p.Ser40Ala missense_variant Exon 2 of 19 ENST00000304858.7 NP_002145.3 P34932-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HSPA4ENST00000304858.7 linkc.118T>G p.Ser40Ala missense_variant Exon 2 of 19 1 NM_002154.4 ENSP00000302961.2 P34932-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 20, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.118T>G (p.S40A) alteration is located in exon 2 (coding exon 2) of the HSPA4 gene. This alteration results from a T to G substitution at nucleotide position 118, causing the serine (S) at amino acid position 40 to be replaced by an alanine (A). 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
0.11
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.19
T;T;.
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.033
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.87
D;D;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.35
T;T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
0.48
N;.;.
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-0.60
N;.;.
REVEL
Benign
0.12
Sift
Benign
0.62
T;.;.
Sift4G
Benign
0.62
T;T;T
Polyphen
0.0010
B;.;.
Vest4
0.39
MutPred
0.67
Loss of disorder (P = 0.0839);Loss of disorder (P = 0.0839);Loss of disorder (P = 0.0839);
MVP
0.32
MPC
1.5
ClinPred
0.64
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.13
gMVP
0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-132400682; API