7-76302870-G-A

Variant names:

• chr7-76302870-G-A
• rs375244209
• NM_001540.5:c.158G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001540.5(HSPB1):​c.158G>A​(p.Gly53Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,425,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G53G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 4.89
• Publications: 6 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: Orphanet, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000296557 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a chain Heat shock protein beta-1 (size 204) in uniprot entity HSPB1_HUMAN there are 29 pathogenic changes around while only 8 benign (78%) in NM_001540.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-76302870-G-A is Pathogenic according to our data. Variant chr7-76302870-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 560408.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB1	NM_001540.5	MANE Select	c.158G>A	p.Gly53Asp	missense	Exon 1 of 3	NP_001531.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB1	ENST00000248553.7	TSL:1 MANE Select	c.158G>A	p.Gly53Asp	missense	Exon 1 of 3	ENSP00000248553.6
	HSPB1	ENST00000447574.1	TSL:1	n.183G>A		non_coding_transcript_exon	Exon 1 of 2
	HSPB1	ENST00000676231.2		c.158G>A	p.Gly53Asp	missense	Exon 1 of 4	ENSP00000502249.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183834 AF XY: 0.00000978

Gnomad AFR exome AF: 0.000103

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000115

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1425836 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707318

African (AFR) AF: 0.0000304 AC: 1 AN: 32946

American (AMR) AF: 0.00 AC: 0 AN: 40874

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 38252

South Asian (SAS) AF: 0.00 AC: 0 AN: 83114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099274

Other (OTH) AF: 0.00 AC: 0 AN: 59114

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000256 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000871 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
1	-	-	Neuronopathy, distal hereditary motor, type 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.72
Sift	Benign	0.050	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.52
MVP		0.98
MPC		1.7
ClinPred		0.99	D
GERP RS		4.8
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.77
gMVP		0.89
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs375244209; hg19: chr7-75932187;