Genetic Variant HSPA8:p.Ala587Ala (chr11-123057914-A-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7

The NM_006597.6(HSPA8):c.1761T>G(p.Ala587Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,453,152 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HSPA8
NM_006597.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.44

Publications

24 publications found

Variant links:

Genes affected

HSPA8 (HGNC:5241): (heat shock protein family A (Hsp70) member 8) This gene encodes a member of the heat shock protein 70 family, which contains both heat-inducible and constitutively expressed members. This protein belongs to the latter group, which are also referred to as heat-shock cognate proteins. It functions as a chaperone, and binds to nascent polypeptides to facilitate correct folding. It also functions as an ATPase in the disassembly of clathrin-coated vesicles during transport of membrane components through the cell. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

HSPA8 links:

SNORD14E (HGNC:30354): (small nucleolar RNA, C/D box 14E)

SNORD14E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP7

Synonymous conserved (PhyloP=-1.44 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA8	NM_006597.6 link	c.1761T>G	p.Ala587Ala	synonymous_variant	Exon 9 of 9	ENST00000534624.6	NP_006588.1	P11142-1V9HW22Q53HF2
HSPA8	XM_011542798.2 link	c.1761T>G	p.Ala587Ala	synonymous_variant	Exon 9 of 9		XP_011541100.1	P11142-1V9HW22
HSPA8	NM_153201.4 link	c.1388-86T>G		intron_variant	Intron 7 of 7		NP_694881.1	P11142-2Q53HF2
SNORD14E	NR_003125.2 link	n.*163T>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA8	ENST00000534624.6 link	c.1761T>G	p.Ala587Ala	synonymous_variant	Exon 9 of 9	1	NM_006597.6	ENSP00000432083.1		P11142-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000412

AC:

AN:

242580

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000551

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000482

AC:

AN:

1453152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722672

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33064

American (AMR)

AF:

0.00

AC:

AN:

42652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25676

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39572

South Asian (SAS)

AF:

0.00

AC:

AN:

84818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00000541

AC:

AN:

1108268

Other (OTH)

AF:

0.00

AC:

AN:

60020

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002848), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.389

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.7

(source)

DANN

Benign

0.53

PhyloP100

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over