Genetic Variant HSPA12B:p.Leu188Leu (chr20-3745918-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The NM_052970.5(HSPA12B):c.562C>T(p.Leu188Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0181 in 1,613,808 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.018 ( 22 hom., cov: 32)

Exomes 𝑓: 0.018 ( 306 hom. )

Consequence

HSPA12B
NM_052970.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.00

Publications

7 publications found

Variant links:

Genes affected

HSPA12B (HGNC:16193): (heat shock protein family A (Hsp70) member 12B) The protein encoded by this gene contains an atypical heat shock protein 70 (Hsp70) ATPase domain and is therefore a distant member of the mammalian Hsp70 family. This gene may be involved in susceptibility to atherosclerosis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

HSPA12B links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.018 (2744/152356) while in subpopulation SAS AF = 0.0276 (133/4822). AF 95% confidence interval is 0.0238. There are 22 homozygotes in GnomAd4. There are 1305 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA12B	NM_052970.5 link	c.562C>T	p.Leu188Leu	synonymous_variant	Exon 7 of 13	ENST00000254963.7	NP_443202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA12B	ENST00000254963.7 link	c.562C>T	p.Leu188Leu	synonymous_variant	Exon 7 of 13	1	NM_052970.5	ENSP00000254963.2
HSPA12B	ENST00000399701.1 link	c.304C>T	p.Leu102Leu	synonymous_variant	Exon 6 of 12	1		ENSP00000382608.1

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2740

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.0188

Gnomad SAS

AF:

0.0276

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0205

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.0182

AC:

4584

AN:

251336

AF XY:

0.0188

show subpopulations

Gnomad AFR exome

AF:

0.0160

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0288

Gnomad EAS exome

AF:

0.0213

Gnomad FIN exome

AF:

0.0108

Gnomad NFE exome

AF:

0.0190

Gnomad OTH exome

AF:

0.0223

GnomAD4 exome

AF:

0.0181

AC:

26444

AN:

1461452

Hom.:

306

Cov.:

AF XY:

0.0184

AC XY:

13399

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.0159

AC:

532

AN:

33470

American (AMR)

AF:

0.0125

AC:

557

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0279

AC:

729

AN:

26132

East Asian (EAS)

AF:

0.0118

AC:

469

AN:

39698

South Asian (SAS)

AF:

0.0239

AC:

2060

AN:

86252

European-Finnish (FIN)

AF:

0.0100

AC:

536

AN:

53348

Middle Eastern (MID)

AF:

0.0322

AC:

186

AN:

5768

European-Non Finnish (NFE)

AF:

0.0181

AC:

20070

AN:

1111680

Other (OTH)

AF:

0.0216

AC:

1305

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1226

2452

3677

4903

6129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

742

1484

2226

2968

3710

<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

AF:

0.0180

AC:

2744

AN:

152356

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1305

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0156

AC:

650

AN:

41584

American (AMR)

AF:

0.0128

AC:

196

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

AN:

3472

East Asian (EAS)

AF:

0.0185

AC:

AN:

5192

South Asian (SAS)

AF:

0.0276

AC:

133

AN:

4822

European-Finnish (FIN)

AF:

0.0120

AC:

128

AN:

10624

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0205

AC:

1393

AN:

68040

Other (OTH)

AF:

0.0208

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

138

277

415

554

692

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0192

Hom.:

Bravo

AF:

0.0175

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.0215

EpiControl

AF:

0.0210

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

4.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over