Genetic Variant HSPBAP1:p.Arg282Pro (chr3-122741094-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_024610.6(HSPBAP1):c.845G>C(p.Arg282Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,524 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HSPBAP1
NM_024610.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.66

Publications

0 publications found

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]

HSPBAP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024610.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPBAP1	NM_024610.6	MANE Select	c.845G>C	p.Arg282Pro	missense	Exon 7 of 8	NP_078886.2
	HSPBAP1	NM_001320728.2		c.761G>C	p.Arg254Pro	missense	Exon 6 of 7	NP_001307657.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSPBAP1	ENST00000306103.3	TSL:1 MANE Select	c.845G>C	p.Arg282Pro	missense	Exon 7 of 8	ENSP00000302562.2	Q96EW2-1
HSPBAP1	ENST00000471534.1	TSL:1	n.683G>C		non_coding_transcript_exon	Exon 1 of 2
HSPBAP1	ENST00000936102.1		c.857G>C	p.Arg286Pro	missense	Exon 7 of 8	ENSP00000606161.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461524

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111680

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.1

PhyloP100

4.7

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.8

REVEL

Benign

0.28

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.80

MutPred

0.45

Gain of helix (P = 0.062)

MVP

0.35

MPC

1.0

ClinPred

0.99

GERP RS

4.5

Varity_R

0.87

gMVP

0.93

Mutation Taster

=48/52

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over