chr3-122740557-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024610.6(HSPBAP1):​c.1255G>T​(p.Asp419Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HSPBAP1
NM_024610.6 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0320
Variant links:
Genes affected
HSPBAP1 (HGNC:16389): (HSPB1 associated protein 1) This gene encodes a protein that binds to one of the small heat shock proteins, specifically hsp27. Hsp27 is involved with cell growth and differentiation. This encoded protein was found to be abnormally expressed in patients with intractable epilepsy, although how brain function is affected remains unknown. [provided by RefSeq, Sep 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06644228).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HSPBAP1NM_024610.6 linkc.1255G>T p.Asp419Tyr missense_variant Exon 8 of 8 ENST00000306103.3 NP_078886.2 Q96EW2-1A8K045

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HSPBAP1ENST00000306103.3 linkc.1255G>T p.Asp419Tyr missense_variant Exon 8 of 8 1 NM_024610.6 ENSP00000302562.2 Q96EW2-1
HSPBAP1ENST00000471534.1 linkn.1093G>T non_coding_transcript_exon_variant Exon 2 of 2 1

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251420
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.000123
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461878
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152318
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.000216
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000680
ExAC
AF:
0.0000247
AC:
3
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jun 05, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1255G>T (p.D419Y) alteration is located in exon 8 (coding exon 8) of the HSPBAP1 gene. This alteration results from a G to T substitution at nucleotide position 1255, causing the aspartic acid (D) at amino acid position 419 to be replaced by a tyrosine (Y). 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
0.077
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
11
DANN
Benign
0.73
DEOGEN2
Benign
0.0047
T
Eigen
Benign
-0.89
Eigen_PC
Benign
-0.95
FATHMM_MKL
Benign
0.055
N
LIST_S2
Benign
0.75
T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.066
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.97
L
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-2.2
N
REVEL
Benign
0.052
Sift
Benign
0.030
D
Sift4G
Uncertain
0.041
D
Polyphen
0.48
P
Vest4
0.15
MutPred
0.23
Loss of disorder (P = 0.0262);
MVP
0.28
MPC
0.40
ClinPred
0.065
T
GERP RS
-0.46
Varity_R
0.060
gMVP
0.25

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: rs769688078; hg19: chr3-122459404; API