Variant 4-127801196-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014278.4(HSPA4L):c.488C>T(p.Ala163Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HSPA4L
NM_014278.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.21

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA4L	NM_014278.4 linkuse as main transcript	c.488C>T	p.Ala163Val	missense_variant	5/19	ENST00000296464.9	NP_055093.2	O95757A0A140VKE7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HSPA4L	ENST00000296464.9 linkuse as main transcript	c.488C>T	p.Ala163Val	missense_variant	5/19	1	NM_014278.4	ENSP00000296464.3	O95757
HSPA4L	ENST00000508549.5 linkuse as main transcript	c.365C>T	p.Ala122Val	missense_variant	4/13	1		ENSP00000427305.1	D6RJ96
HSPA4L	ENST00000508776.5 linkuse as main transcript	c.488C>T	p.Ala163Val	missense_variant	6/20	2		ENSP00000422482.1	O95757
HSPA4L	ENST00000505726.1 linkuse as main transcript	c.410C>T	p.Ala137Val	missense_variant	5/19	2		ENSP00000425645.1	E9PDE8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

249980

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000582

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460608

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726636

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000449

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

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

Sep 11, 2024

The c.488C>T (p.A163V) alteration is located in exon 5 (coding exon 5) of the HSPA4L gene. This alteration results from a C to T substitution at nucleotide position 488, causing the alanine (A) at amino acid position 163 to be replaced by a valine (V). 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

Uncertain

0.36

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

.;D;D;D

M_CAP

Benign

0.0036

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.1

M;M;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Uncertain

0.41

Sift

Benign

0.21

T;T;T;T

Sift4G

Benign

0.13

T;T;T;T

Polyphen

1.0

D;D;.;D

Vest4

0.98

MutPred

0.84

Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);.;.;

MVP

0.69

MPC

0.58

ClinPred

0.99

GERP RS

5.2

Varity_R

0.56

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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