Genetic Variant HSPA1A:c.-97T>C (chr6-31815660-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_005345.6(HSPA1A):c.-97T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,612,906 control chromosomes in the GnomAD database, including 543 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 0.028 ( 84 hom., cov: 32)

Exomes 𝑓: 0.022 ( 459 hom. )

Consequence

HSPA1A
NM_005345.6 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.54

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0282 (4299/152354) while in subpopulation AMR AF = 0.0487 (745/15304). AF 95% confidence interval is 0.0458. There are 84 homozygotes in GnomAd4. There are 2057 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4299 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA1A	NM_005345.6 link	c.-97T>C		5_prime_UTR_variant	Exon 1 of 1	ENST00000375651.7	NP_005336.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA1A	ENST00000375651.7 link	c.-97T>C		5_prime_UTR_variant	Exon 1 of 1	6	NM_005345.6	ENSP00000364802.5
HSPA1A	ENST00000608703.2 link	c.-97T>C		5_prime_UTR_variant	Exon 1 of 2	2		ENSP00000477378.1

Frequencies

GnomAD3 genomes

AF:

0.0283

AC:

4309

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0395

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0487

Gnomad ASJ

AF:

0.0449

Gnomad EAS

AF:

0.00943

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0223

Gnomad OTH

AF:

0.0392

GnomAD4 exome

AF:

0.0216

AC:

31621

AN:

1460552

Hom.:

459

Cov.:

AF XY:

0.0214

AC XY:

15563

AN XY:

726588

show subpopulations

African (AFR)

AF:

0.0428

AC:

1434

AN:

33466

American (AMR)

AF:

0.0339

AC:

1513

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

1205

AN:

26116

East Asian (EAS)

AF:

0.00383

AC:

152

AN:

39692

South Asian (SAS)

AF:

0.0167

AC:

1440

AN:

86226

European-Finnish (FIN)

AF:

0.00334

AC:

175

AN:

52430

Middle Eastern (MID)

AF:

0.0427

AC:

246

AN:

5766

European-Non Finnish (NFE)

AF:

0.0216

AC:

24043

AN:

1111828

Other (OTH)

AF:

0.0234

AC:

1413

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1817

3634

5451

7268

9085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

928

1856

2784

3712

4640

<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:

0.0282

AC:

4299

AN:

152354

Hom.:

Cov.:

AF XY:

0.0276

AC XY:

2057

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0393

AC:

1635

AN:

41582

American (AMR)

AF:

0.0487

AC:

745

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0449

AC:

156

AN:

3472

East Asian (EAS)

AF:

0.00945

AC:

AN:

5186

South Asian (SAS)

AF:

0.0145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00282

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0223

AC:

1515

AN:

68028

Other (OTH)

AF:

0.0383

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

211

422

633

844

1055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0236

Hom.:

Bravo

AF:

0.0330

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

3.7

(source)

DANN

Benign

0.64

PhyloP100

-1.5

PromoterAI

-0.22

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(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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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