Variant 4-127808025-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014278.4(HSPA4L):c.1274C>T(p.Pro425Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

HSPA4L
NM_014278.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.54

Variant links:

Genes affected

HSPA4L (HGNC:17041): (heat shock protein family A (Hsp70) member 4 like) The protein encoded by this gene is heat shock inducible and may act as a chaperone. The encoded protein can protect the heat-shocked cell against the harmful effects of aggregated proteins. This gene is highly expressed in leukemia cells and may be a good target for therapeutic intervention. Several transcripts encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

HSPA4L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13628998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA4L	NM_014278.4 linkuse as main transcript	c.1274C>T	p.Pro425Leu	missense_variant	11/19	ENST00000296464.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HSPA4L	ENST00000296464.9 linkuse as main transcript	c.1274C>T	p.Pro425Leu	missense_variant	11/19	1	NM_014278.4	P1
HSPA4L	ENST00000508549.5 linkuse as main transcript	c.1151C>T	p.Pro384Leu	missense_variant	10/13	1
HSPA4L	ENST00000508776.5 linkuse as main transcript	c.1274C>T	p.Pro425Leu	missense_variant	12/20	2		P1
HSPA4L	ENST00000505726.1 linkuse as main transcript	c.1196C>T	p.Pro399Leu	missense_variant	11/19	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152120

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:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000560

AC:

AN:

250038

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000763

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1460148

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726346

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000606

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000770

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2022

The c.1274C>T (p.P425L) alteration is located in exon 11 (coding exon 11) of the HSPA4L gene. This alteration results from a C to T substitution at nucleotide position 1274, causing the proline (P) at amino acid position 425 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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.42

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.19

T;T;T;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.010

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.6

L;L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.6

D;D;D;D

REVEL

Benign

0.13

Sift

Benign

0.045

D;D;T;D

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.31

B;B;.;P

Vest4

0.39

MutPred

0.64

Loss of catalytic residue at N423 (P = 0.1062);Loss of catalytic residue at N423 (P = 0.1062);.;.;

MVP

0.53

MPC

0.16

ClinPred

0.22

GERP RS

5.0

Varity_R

0.18

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over