Genetic Variant HSPB6:p.Ser143Pro (chr19-35755578-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_144617.3(HSPB6):c.427T>C(p.Ser143Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 150,344 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 0.000027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HSPB6
NM_144617.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.12

Publications

0 publications found

Variant links:

Genes affected

HSPB6 (HGNC:26511): (heat shock protein family B (small) member 6) This locus encodes a heat shock protein. The encoded protein likely plays a role in smooth muscle relaxation. [provided by RefSeq, Jan 2012]

HSPB6 links:

ENSG00000267328 (HGNC:):

ENSG00000267328 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144617.3. 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
	HSPB6	NM_144617.3	MANE Select	c.427T>C	p.Ser143Pro	missense	Exon 3 of 3	NP_653218.1	O14558

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSPB6	ENST00000004982.6	TSL:1 MANE Select	c.427T>C	p.Ser143Pro	missense	Exon 3 of 3	ENSP00000004982.3	O14558
HSPB6	ENST00000906439.1		c.304T>C	p.Ser102Pro	missense	Exon 2 of 2	ENSP00000576498.1
HSPB6	ENST00000587965.1	TSL:2	c.*101T>C		3_prime_UTR	Exon 2 of 2	ENSP00000467169.1	K7EP04

Frequencies

GnomAD3 genomes

AF:

0.0000266

AC:

AN:

150344

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000976

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1338334

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

660916

African (AFR)

AF:

0.00

AC:

AN:

29254

American (AMR)

AF:

0.00

AC:

AN:

34212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23392

East Asian (EAS)

AF:

0.00

AC:

AN:

31582

South Asian (SAS)

AF:

0.00

AC:

AN:

78334

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5460

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1053300

Other (OTH)

AF:

0.00

AC:

AN:

54468

GnomAD4 genome

AF:

0.0000266

AC:

AN:

150344

Hom.:

Cov.:

AF XY:

0.0000545

AC XY:

AN XY:

73388

show subpopulations

African (AFR)

AF:

0.0000976

AC:

AN:

40966

American (AMR)

AF:

0.00

AC:

AN:

15118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

4840

South Asian (SAS)

AF:

0.00

AC:

AN:

4558

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67644

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.8

PhyloP100

3.1

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0060

Polyphen

0.99

Vest4

0.66

MutPred

0.51

Loss of glycosylation at S143 (P = 0.0335)

MVP

1.0

ClinPred

0.98

GERP RS

4.5

Varity_R

0.89

gMVP

0.81

Mutation Taster

=49/51

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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