chr5-54455916-G-C

Variant names:

• chr5-54455916-G-C
• rs372203645
• NM_006308.3:c.127G>C

Variant summary

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

The NM_006308.3(HSPB3):​c.127G>C​(p.Val43Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HSPB3 NM_006308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243

Genes affected

HSPB3 (HGNC:5248): (heat shock protein family B (small) member 3) This gene encodes a muscle-specific small heat shock protein. A mutation in this gene is the cause of autosomal dominant distal hereditary motor neuropathy type 2C.[provided by RefSeq, Sep 2010]

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=0.07044336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB3	NM_006308.3	c.127G>C	p.Val43Leu	missense_variant	Exon 1 of 1	ENST00000302005.3	NP_006299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPB3	ENST00000302005.3	c.127G>C	p.Val43Leu	missense_variant	Exon 1 of 1	6	NM_006308.3	ENSP00000303394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	6.8
DANN	Benign	0.66
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.25
Sift	Benign	0.71	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.019
MutPred		0.37		Gain of ubiquitination at K47 (P = 0.1108);
MVP		0.56
MPC		0.086
ClinPred		0.028	T
GERP RS		4.3
Varity_R		0.044
gMVP		0.36

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: rs372203645; hg19: chr5-53751746;