Variant 4-127811540-C-A 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.1482C>A(p.Ser494Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,613,562 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 0.00024 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

HSPA4L
NM_014278.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.672

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=0.09493652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA4L	NM_014278.4 linkuse as main transcript	c.1482C>A	p.Ser494Arg	missense_variant	12/19	ENST00000296464.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HSPA4L	ENST00000296464.9 linkuse as main transcript	c.1482C>A	p.Ser494Arg	missense_variant	12/19	1	NM_014278.4	P1
HSPA4L	ENST00000508549.5 linkuse as main transcript	c.1359C>A	p.Ser453Arg	missense_variant	11/13	1
HSPA4L	ENST00000508776.5 linkuse as main transcript	c.1482C>A	p.Ser494Arg	missense_variant	13/20	2		P1
HSPA4L	ENST00000505726.1 linkuse as main transcript	c.1404C>A	p.Ser468Arg	missense_variant	12/19	2

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251298

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000387

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000460

AC:

673

AN:

1461510

Hom.:

Cov.:

AF XY:

0.000432

AC XY:

314

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000578

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000237

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000451

Hom.:

Bravo

AF:

0.000249

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

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

Jul 12, 2022

The c.1482C>A (p.S494R) alteration is located in exon 12 (coding exon 12) of the HSPA4L gene. This alteration results from a C to A substitution at nucleotide position 1482, causing the serine (S) at amino acid position 494 to be replaced by an arginine (R). 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

Pathogenic

0.91

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T;T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.73

M_CAP

Benign

0.019

MetaRNN

Benign

0.095

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.4

L;L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.7

D;D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0070

D;D;T;D

Polyphen

0.98

D;D;.;D

Vest4

0.50

MutPred

0.73

Gain of MoRF binding (P = 0.0185);Gain of MoRF binding (P = 0.0185);.;.;

MVP

0.49

MPC

0.64

ClinPred

0.34

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.64

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