5-133067510-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002154.4(HSPA4):​c.259C>T​(p.Leu87Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

HSPA4
NM_002154.4 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.01
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HSPA4NM_002154.4 linkuse as main transcriptc.259C>T p.Leu87Phe missense_variant 3/19 ENST00000304858.7 NP_002145.3 P34932-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HSPA4ENST00000304858.7 linkuse as main transcriptc.259C>T p.Leu87Phe missense_variant 3/191 NM_002154.4 ENSP00000302961.2 P34932-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251380
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461600
Hom.:
0
Cov.:
30
AF XY:
0.00000550
AC XY:
4
AN XY:
727112
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 GeneticsJul 10, 2024The c.259C>T (p.L87F) alteration is located in exon 3 (coding exon 3) of the HSPA4 gene. This alteration results from a C to T substitution at nucleotide position 259, causing the leucine (L) at amino acid position 87 to be replaced by a phenylalanine (F). 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
0.18
BayesDel_addAF
Benign
0.00081
T
BayesDel_noAF
Benign
-0.22
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.30
T;T;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Benign
0.020
T
MetaRNN
Pathogenic
0.80
D;D;D
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
1.4
L;.;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-2.9
D;.;.
REVEL
Benign
0.24
Sift
Benign
0.030
D;.;.
Sift4G
Benign
0.20
T;T;T
Polyphen
1.0
D;.;.
Vest4
0.66
MutPred
0.69
Gain of catalytic residue at L87 (P = 0.027);Gain of catalytic residue at L87 (P = 0.027);Gain of catalytic residue at L87 (P = 0.027);
MVP
0.62
MPC
0.85
ClinPred
0.80
D
GERP RS
6.0
Varity_R
0.39
gMVP
0.63

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: rs758331796; hg19: chr5-132403202; API