Genetic Variant NM_144617.3:c.322G>A (chr19-35755683-C-T) – 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_144617.3(HSPB6):c.322G>A(p.Asp108Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000217 in 1,382,112 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

HSPB6
NM_144617.3 missense, splice_region

Scores

Splicing: ADA: 0.9983

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.55

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:

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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

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.322G>A	p.Asp108Asn	missense splice_region	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.322G>A	p.Asp108Asn	missense splice_region	Exon 3 of 3	ENSP00000004982.3	O14558
HSPB6	ENST00000587965.1	TSL:2	c.410G>A	p.Gly137Glu	missense	Exon 2 of 2	ENSP00000467169.1	K7EP04
HSPB6	ENST00000592984.6	TSL:4	c.322G>A	p.Asp108Asn	missense splice_region	Exon 4 of 4	ENSP00000468057.2	A0A1X7SC65

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000217

AC:

AN:

1382112

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

681608

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29878

American (AMR)

AF:

0.00

AC:

AN:

34990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24658

East Asian (EAS)

AF:

0.00

AC:

AN:

34714

South Asian (SAS)

AF:

0.0000257

AC:

AN:

77854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

9.31e-7

AC:

AN:

1074572

Other (OTH)

AF:

0.00

AC:

AN:

57468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

0.98

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.74

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.5

PhyloP100

4.5

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.33

MutPred

0.67

Gain of MoRF binding (P = 0.0598)

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

4.5

Varity_R

0.92

gMVP

0.53

Mutation Taster

=50/50

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over