Genetic Variant NM_014424.5:c.134T>C (chr1-16017830-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014424.5(HSPB7):c.134T>C(p.Leu45Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,330 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

HSPB7
NM_014424.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25

Publications

1 publications found

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]

HSPB7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014424.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSPB7	NM_014424.5	MANE Select	c.134T>C	p.Leu45Pro	missense	Exon 1 of 3	NP_055239.1	Q9UBY9-1
HSPB7	NM_001349682.2		c.359T>C	p.Leu120Pro	missense	Exon 2 of 4	NP_001336611.1	Q8N241
HSPB7	NM_001349689.2		c.134T>C	p.Leu45Pro	missense	Exon 1 of 3	NP_001336618.1	Q9UBY9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSPB7	ENST00000311890.14	TSL:1 MANE Select	c.134T>C	p.Leu45Pro	missense	Exon 1 of 3	ENSP00000310111.9	Q9UBY9-1
HSPB7	ENST00000487046.1	TSL:1	c.134T>C	p.Leu45Pro	missense	Exon 1 of 3	ENSP00000419477.1	Q9UBY9-2
HSPB7	ENST00000406363.2	TSL:1	c.134T>C	p.Leu45Pro	missense	Exon 1 of 3	ENSP00000385472.2	Q68DG0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000406

AC:

AN:

246546

AF XY:

0.00000747

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000909

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461330

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1111764

Other (OTH)

AF:

0.0000166

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000378

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

Benign

0.077

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.49

MetaRNN

Uncertain

0.65

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

1.9

PhyloP100

2.3

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.080

REVEL

Uncertain

0.61

Sift

Benign

0.20

Sift4G

Benign

0.13

Polyphen

0.98

Vest4

0.60

MutPred

0.33

Loss of stability (P = 0.0307)

MVP

0.96

MPC

0.74

ClinPred

0.52

GERP RS

4.6

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.40

gMVP

0.67

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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