rs121909112

Variant names:

• chr7-76303855-C-G
• rs121909112
• NM_001540.5:c.418C>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001540.5(HSPB1):​c.418C>G​(p.Arg140Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000242 in 1,240,538 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: "SCV000816282: Experimental studies have shown that this missense change affects HSPB1 function (PMID:23643870, 28595321)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.93
• Publications: 28 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000816282: Experimental studies have shown that this missense change affects HSPB1 function (PMID: 23643870, 28595321).; SCV000999000: The said variant affects the quaternary structure and decreases the chaperon like activity of the protein (Nefedova et al 2013 Biochimie).; SCV005883290: The most pronounced variant effect results in significantly diminished normal HSPB1 activity, forming aggregates, and loss of the binding with wide-type HspB6 in vitro (Nefedova_2013). PMID: 29184351, 28018906, 23948568, 35297556; SCV003761876: Published functional studies demonstrate a damaging effect, including decreased chaperone-like activity and impaired mitochondrial function in motor neurons (Nefedova et al., 2013; Kalmar et al., 2017); SCV004229711: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23643870, 28595321); SCV002034853: Experiments expressing the variant in a heterologous state using a lentiviral system in primary cultured mouse motor neurons showed that, in this model, p.Arg140Gly reduced the speed and altered the pausing frequency of retrograde axonal mitochondrial transport, leading to an increased vulnerability of these cells to oxidative stress (Kalmar et al. 2017).; SCV002627013: Functional studies suggest this alteration impairs mitochondrial function and results in a reduction of chaperone-like activity (Kalmar B et al. Hum Mol Genet 2017 Sep; 26:3313-3326; Nefedova V et al. Biochimie 2013 Aug;95:1582-1592).
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_001540.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-76303855-C-G is Pathogenic according to our data. Variant chr7-76303855-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7484.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.418C>G	p.Arg140Gly	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.418C>G	p.Arg140Gly	missense	Exon 2 of 3	ENSP00000248553.6	P04792
	HSPB1	ENST00000429938.1	TSL:1	c.-87C>G		5_prime_UTR	Exon 2 of 3	ENSP00000405285.1	C9J3N8
	HSPB1	ENST00000447574.1	TSL:1	n.1168C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000242 AC: 3 AN: 1240538 Hom.: 0 Cov.: 36 AF XY: 0.00000486 AC XY: 3 AN XY: 617200

African (AFR) AF: 0.00 AC: 0 AN: 28084

American (AMR) AF: 0.00 AC: 0 AN: 40188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20184

East Asian (EAS) AF: 0.00 AC: 0 AN: 26306

South Asian (SAS) AF: 0.0000361 AC: 3 AN: 83130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 951018

Other (OTH) AF: 0.00 AC: 0 AN: 47958

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Charcot-Marie-Tooth disease axonal type 2F (3)
1	-	-	Charcot-Marie-Tooth disease (1)
1	-	-	Charcot-Marie-Tooth disease axonal type 2F;C2608087:Neuronopathy, distal hereditary motor, type 2B (1)
1	-	-	HSPB1-related axonal neuropathies (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neuronopathy, distal hereditary motor, type 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		2.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.15	B
Vest4		0.93
MutPred		0.97		Loss of methylation at K141 (P = 0.0471)
MVP		0.99
MPC		0.74
ClinPred		0.90	D
GERP RS		3.5
PromoterAI		-0.068	Neutral
Varity_R		0.97
gMVP		0.91
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs121909112; hg19: chr7-75933172; COSMIC: COSV105065418;