NM_001540.5:c.379C>T

Variant names:

• chr7-76303816-C-T
• rs29001571
• NM_001540.5:c.379C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001540.5(HSPB1):​c.379C>T​(p.Arg127Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001582548: Experimental studies have shown that this missense change affects HSPB1 function (PMID:20178975, 22031878)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.721
• Publications: 47 publications found

Genes affected

HSPB1 (HGNC:5246): (heat shock protein family B (small) member 1) This gene encodes a member of the small heat shock protein (HSP20) family of proteins. In response to environmental stress, the encoded protein translocates from the cytoplasm to the nucleus and functions as a molecular chaperone that promotes the correct folding of other proteins. This protein plays an important role in the differentiation of a wide variety of cell types. Expression of this gene is correlated with poor clinical outcome in multiple human cancers, and the encoded protein may promote cancer cell proliferation and metastasis, while protecting cancer cells from apoptosis. Mutations in this gene have been identified in human patients with Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. [provided by RefSeq, Aug 2017]

HSPB1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2F

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• neuronopathy, distal hereditary motor, type 2B

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• distal hereditary motor neuropathy type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001582548: Experimental studies have shown that this missense change affects HSPB1 function (PMID: 20178975, 22031878).; SCV000577216: Published functional studies demonstrate a damaging effect: hyperphosphorylation and reduced anterograde transport of neurofilaments, disturbed microtubule dynamics, and defective autophagy (PMID: 30669930, 20178975, 22031878, 23728742); SCV000613674: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 30669930, 29330367, 29048431).; SCV004564308: Functional analyses found the variant protein disrupts microtubule dynamics and reduces anterograde transport of neurofilaments (Almedia-Souza 2011, Holmgren 2013). PMID: 22031878. PMID: 15122254. PMID: 23728742.; SCV002620136: "In vitro experimental studies show that this alteration affects neurofilament interaction with kinesin, destabilizes intersubunit contacts, and may induce HspB1 monomerization (Almeida-Souza L et al. J Biol Chem, 2010 Apr;285:12778-86; Almeida-Souza L et al. J Neurosci, 2011 Oct;31:15320-8; Holmgren A et al. Acta Neuropathol, 2013 Jul;126:93-108)."
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_001540.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-76303817-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 157529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 7-76303816-C-T is Pathogenic according to our data. Variant chr7-76303816-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001540.5. 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
	HSPB1	NM_001540.5	MANE Select	c.379C>T	p.Arg127Trp	missense	Exon 2 of 3	NP_001531.1	P04792

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB1	ENST00000248553.7	TSL:1 MANE Select	c.379C>T	p.Arg127Trp	missense	Exon 2 of 3	ENSP00000248553.6	P04792
	HSPB1	ENST00000429938.1	TSL:1	c.-126C>T		5_prime_UTR	Exon 2 of 3	ENSP00000405285.1	C9J3N8
	HSPB1	ENST00000447574.1	TSL:1	n.1129C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Charcot-Marie-Tooth disease axonal type 2F (4)
3	-	-	not provided (3)
2	-	-	Neuronopathy, distal hereditary motor, type 2B (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		0.72
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.85		Loss of disorder (P = 0.0191)
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		-5.7
PromoterAI		-0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.72
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs29001571; hg19: chr7-75933133;