Genetic Variant NM_005345.6:c.242C>T (chr6-31815998-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005345.6(HSPA1A):c.242C>T(p.Pro81Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 12)

Exomes 𝑓: 0.0000033 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HSPA1A
NM_005345.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

Publications

0 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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23411313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA1A	NM_005345.6 link	c.242C>T	p.Pro81Leu	missense_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.242C>T	p.Pro81Leu	missense_variant	Exon 1 of 1	6	NM_005345.6	ENSP00000364802.5		P0DMV8-1
HSPA1A	ENST00000608703.2 link	c.75+167C>T		intron_variant	Intron 1 of 1	2		ENSP00000477378.1		V9GZ37

Frequencies

GnomAD3 genomes

AF:

0.00000901

AC:

AN:

111022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000351

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000329

AC:

AN:

1216100

Hom.:

Cov.:

AF XY:

0.00000666

AC XY:

AN XY:

600282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28150

American (AMR)

AF:

0.00

AC:

AN:

33434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21520

East Asian (EAS)

AF:

0.00

AC:

AN:

34702

South Asian (SAS)

AF:

0.0000427

AC:

AN:

70248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3640

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

934132

Other (OTH)

AF:

0.00

AC:

AN:

51738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

111112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

51772

African (AFR)

AF:

0.00

AC:

AN:

27770

American (AMR)

AF:

0.00

AC:

AN:

10434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2928

East Asian (EAS)

AF:

0.00

AC:

AN:

3962

South Asian (SAS)

AF:

0.00

AC:

AN:

2840

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6776

Middle Eastern (MID)

AF:

0.00

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

54058

Other (OTH)

AF:

0.00

AC:

AN:

1394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.242C>T (p.P81L) alteration is located in exon 1 (coding exon 1) of the HSPA1A gene. This alteration results from a C to T substitution at nucleotide position 242, causing the proline (P) at amino acid position 81 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

Eigen

Benign

-0.072

Eigen_PC

Benign

-0.084

FATHMM_MKL

Benign

0.66

M_CAP

Benign

0.012

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

PhyloP100

2.6

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.16

Sift

Uncertain

0.016

Sift4G

Uncertain

0.021

Vest4

0.26

MutPred

0.36

Gain of MoRF binding (P = 0.0561);

MVP

0.64

ClinPred

0.91

GERP RS

3.2

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.12

gMVP

0.53

Mutation Taster

=92/8

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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NM_005345.6:c.242C>T

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