4-127818394-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014278.4(HSPA4L):c.1648A>G(p.Ile550Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,456,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: HSPA4L NM_014278.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

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]

ACMG classification

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=0.10304043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA4L	NM_014278.4	c.1648A>G	p.Ile550Val	missense_variant	13/19	ENST00000296464.9
HSPA4L	NM_001317381.2	c.1741A>G	p.Ile581Val	missense_variant	14/20
HSPA4L	NM_001317382.2	c.1570A>G	p.Ile524Val	missense_variant	13/19
HSPA4L	NM_001317383.2	c.1525A>G	p.Ile509Val	missense_variant	12/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPA4L	ENST00000296464.9	c.1648A>G	p.Ile550Val	missense_variant	13/19	1	NM_014278.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1456378 Hom.: 0 Cov.: 29 AF XY: 0.00000552 AC XY: 4 AN XY: 724430

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000812

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

The c.1648A>G (p.I550V) alteration is located in exon 13 (coding exon 13) of the HSPA4L gene. This alteration results from a A to G substitution at nucleotide position 1648, causing the isoleucine (I) at amino acid position 550 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	Benign	0.067
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.027	T;T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.0	L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.47	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.22
MutPred		0.36		Loss of catalytic residue at I550 (P = 0.0977);Loss of catalytic residue at I550 (P = 0.0977);.;.;
MVP		0.46
MPC		0.12
ClinPred		0.56	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.12

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-128739549;