Genetic Variant HSPA1A:p.Gln351Gln (chr6-31816809-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP7

The NM_005345.6(HSPA1A):c.1053G>A(p.Gln351Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HSPA1A
NM_005345.6 synonymous

Scores

Clinical Significance

association no assertion criteria provided O:1

Conservation

PhyloP100: 0.527

Publications

69 publications found

Variant links:

Genes affected

HSPA1A (HGNC:5232): (heat shock protein family A (Hsp70) member 1A) This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family. In conjuction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins. [provided by RefSeq, Jul 2008]

HSPA1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.055).

BP7

Synonymous conserved (PhyloP=0.527 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA1A	NM_005345.6 link	c.1053G>A	p.Gln351Gln	synonymous_variant	Exon 1 of 1	ENST00000375651.7	NP_005336.3	P0DMV8-1P0DMV9A8K5I0B3KTT5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA1A	ENST00000375651.7 link	c.1053G>A	p.Gln351Gln	synonymous_variant	Exon 1 of 1	6	NM_005345.6	ENSP00000364802.5		P0DMV8-1
HSPA1A	ENST00000608703.2 link	c.558G>A	p.Gln186Gln	synonymous_variant	Exon 2 of 2	2		ENSP00000477378.1		V9GZ37

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0127

AC:

242

AN:

19080

AF XY:

0.0114

show subpopulations

Gnomad AFR exome

AF:

0.00113

Gnomad AMR exome

AF:

0.00984

Gnomad ASJ exome

AF:

0.0200

Gnomad EAS exome

AF:

0.0193

Gnomad FIN exome

AF:

0.0220

Gnomad NFE exome

AF:

0.0137

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0150

AC:

1431

AN:

95294

Hom.:

Cov.:

AF XY:

0.0151

AC XY:

766

AN XY:

50784

show subpopulations

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

African (AFR)

AF:

0.00268

AC:

AN:

4112

American (AMR)

AF:

0.00746

AC:

AN:

3888

Ashkenazi Jewish (ASJ)

AF:

0.0269

AC:

AN:

1860

East Asian (EAS)

AF:

0.0142

AC:

AN:

4364

South Asian (SAS)

AF:

0.0206

AC:

346

AN:

16828

European-Finnish (FIN)

AF:

0.00964

AC:

AN:

4148

Middle Eastern (MID)

AF:

0.0325

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0149

AC:

818

AN:

55016

Other (OTH)

AF:

0.0136

AC:

AN:

4770

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.291

Heterozygous variant carriers

160

320

479

639

799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Chronic obstructive pulmonary disease

Other:1

Aug 04, 2019

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance:association

Review Status:no assertion criteria provided

Collection Method:case-control

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.0

(source)

DANN

Benign

0.93

PhyloP100

0.53

Mutation Taster

=100/0

polymorphism

(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

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chr6-31816809-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over