chr5-133067442-T-C

Variant names:

• chr5-133067442-T-C
• rs1765321513
• NM_002154.4:c.191T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002154.4(HSPA4):​c.191T>C​(p.Val64Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPA4 NM_002154.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002154.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA4	NM_002154.4	MANE Select	c.191T>C	p.Val64Ala	missense	Exon 3 of 19	NP_002145.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA4	ENST00000304858.7	TSL:1 MANE Select	c.191T>C	p.Val64Ala	missense	Exon 3 of 19	ENSP00000302961.2	P34932-1
	HSPA4	ENST00000968145.1		c.191T>C	p.Val64Ala	missense	Exon 3 of 20	ENSP00000638204.1
	HSPA4	ENST00000936301.1		c.191T>C	p.Val64Ala	missense	Exon 3 of 19	ENSP00000606360.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.57	P
Vest4		0.77
MutPred		0.88		Gain of disorder (P = 0.0324)
MVP		0.79
MPC		0.84
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.51
gMVP		0.83
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs1765321513; hg19: chr5-132403134;