chr5-133073311-A-T

Position:

• chr5-133073311-A-T

Variant summary

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

The NM_002154.4(HSPA4):​c.511A>T​(p.Met171Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPA4 NM_002154.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.01

Genes affected

HSPA4 (HGNC:5237): (heat shock protein family A (Hsp70) member 4) Predicted to enable ATP binding activity. Involved in chaperone-mediated protein complex assembly and protein insertion into mitochondrial outer membrane. Located in cytosol and extracellular exosome. Implicated in Chagas disease. Biomarker of chronic obstructive pulmonary disease; rheumatoid arthritis; type 2 diabetes mellitus; and ulcerative colitis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA4	NM_002154.4	c.511A>T	p.Met171Leu	missense_variant	5/19	ENST00000304858.7	NP_002145.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPA4	ENST00000304858.7	c.511A>T	p.Met171Leu	missense_variant	5/19	1	NM_002154.4	ENSP00000302961.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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

Jul 05, 2024

The c.511A>T (p.M171L) alteration is located in exon 5 (coding exon 5) of the HSPA4 gene. This alteration results from a A to T substitution at nucleotide position 511, causing the methionine (M) at amino acid position 171 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	0.18
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.22	T;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.078
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.76	N;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N;.;.
REVEL	Benign	0.24
Sift	Benign	0.16	T;.;.
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.50
MutPred		0.59		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.61
MPC		0.26
ClinPred		0.79	D
GERP RS		4.6
Varity_R		0.22
gMVP		0.54

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: chr5-132409003;