chr5-54455953-C-T

Variant names:

• chr5-54455953-C-T
• NM_006308.3:c.164C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006308.3(HSPB3):​c.164C>T​(p.Pro55Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPB3 NM_006308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0490
• Publications: 0 publications found

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]

HSPB3 Gene-Disease associations (from GenCC):

• distal hereditary motor neuropathy type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neuronopathy, distal hereditary motor, type 2C

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05964154).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006308.3. 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
	HSPB3	NM_006308.3	MANE Select	c.164C>T	p.Pro55Leu	missense	Exon 1 of 1	NP_006299.1	Q6ICS9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB3	ENST00000302005.3	TSL:6 MANE Select	c.164C>T	p.Pro55Leu	missense	Exon 1 of 1	ENSP00000303394.1	Q12988

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	Benign	0.065
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.8
DANN	Benign	0.59
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.84	L
PhyloP100		-0.049
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.12
Sift	Benign	0.28	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.034
MutPred		0.28		Loss of catalytic residue at P54 (P = 0.016)
MVP		0.51
MPC		0.089
ClinPred		0.44	T
GERP RS		-3.8
PromoterAI		-0.038	Neutral
Varity_R		0.035
gMVP		0.28
Mutation Taster		=98/2	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

hg19: chr5-53751783;