chr5-133070378-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 16/22 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
• 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.113895535).

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.311C>G	p.Thr104Arg	missense	Exon 4 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.311C>G	p.Thr104Arg	missense	Exon 4 of 19	ENSP00000302961.2	P34932-1
	HSPA4	ENST00000968145.1		c.311C>G	p.Thr104Arg	missense	Exon 4 of 20	ENSP00000638204.1
	HSPA4	ENST00000936301.1		c.311C>G	p.Thr104Arg	missense	Exon 4 of 19	ENSP00000606360.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 43508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1110720

Other (OTH) AF: 0.0000166 AC: 1 AN: 60196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000204244), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00 AC: 0 AN: 41268

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.35	N
PhyloP100		2.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.061
Sift	Benign	0.87	T
Sift4G	Benign	0.99	T
Polyphen		0.010	B
Vest4		0.22
MutPred		0.29		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
Mutation Taster		=85/15	polymorphism

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: rs1459462893; hg19: chr5-132406070;