chr1-16017082-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014424.5(HSPB7):​c.325G>A​(p.Ala109Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000621 in 1,609,050 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: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HSPB7
NM_014424.5 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.77
Variant links:
Genes affected
HSPB7 (HGNC:5249): (heat shock protein family B (small) member 7) This gene encodes a small heat shock family B member that can heterodimerize with similar heat shock proteins. Defects in this gene are associated with advanced heart failure. In addition, the encoded protein may be a tumor suppressor in the p53 pathway, with defects in this gene being associated with renal cell carcinoma. [provided by RefSeq, Mar 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HSPB7NM_014424.5 linkuse as main transcriptc.325G>A p.Ala109Thr missense_variant 2/3 ENST00000311890.14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HSPB7ENST00000311890.14 linkuse as main transcriptc.325G>A p.Ala109Thr missense_variant 2/31 NM_014424.5 P3Q9UBY9-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
151864
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000442
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250750
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135514
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1457186
Hom.:
0
Cov.:
32
AF XY:
0.00000414
AC XY:
3
AN XY:
723984
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00000271
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
151864
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74174
show subpopulations
Gnomad4 AFR
AF:
0.0000484
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000442
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151

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 GeneticsMar 25, 2022The c.325G>A (p.A109T) alteration is located in exon 2 (coding exon 2) of the HSPB7 gene. This alteration results from a G to A substitution at nucleotide position 325, causing the alanine (A) at amino acid position 109 to be replaced by a threonine (T). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.69
D;.;.;.
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D;D;D
M_CAP
Pathogenic
0.49
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Uncertain
2.5
M;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-2.9
D;D;D;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0040
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;.;.
Vest4
0.95
MutPred
0.87
.;Gain of phosphorylation at A184 (P = 0.0841);.;.;
MVP
0.96
MPC
1.1
ClinPred
0.97
D
GERP RS
5.2
Varity_R
0.46
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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: rs1412332304; hg19: chr1-16343577; API