chr5-133070378-C-G

Variant names:

• chr5-133070378-C-G
• rs1459462893
• NM_002154.4:c.311C>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002154.4(HSPA4):​c.311C>G​(p.Thr104Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,609,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T104K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: HSPA4 NM_002154.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.113895535).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA4	NM_002154.4	c.311C>G	p.Thr104Arg	missense_variant	Exon 4 of 19	ENST00000304858.7	NP_002145.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA4	ENST00000304858.7	c.311C>G	p.Thr104Arg	missense_variant	Exon 4 of 19	1	NM_002154.4	ENSP00000302961.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151698 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1457776 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 725350

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: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151698 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74046

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.81
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.35	N;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.3	N;.;.
REVEL	Benign	0.061
Sift	Benign	0.87	T;.;.
Sift4G	Benign	0.99	T;T;T
Polyphen		0.010	B;.;.
Vest4		0.22
MutPred		0.29		Gain of ubiquitination at K102 (P = 0.0645);Gain of ubiquitination at K102 (P = 0.0645);Gain of ubiquitination at K102 (P = 0.0645);
MVP		0.22
MPC		0.36
ClinPred		0.080	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.45

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

Other links and lift over

dbSNP: rs1459462893; hg19: chr5-132406070;