rs778311776

Variant names:

• chr7-76302851-G-A
• rs778311776
• NM_001540.5:c.139G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_001540.5(HSPB1):​c.139G>A​(p.Gly47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,442,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.139
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001540.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.053242117).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

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.139G>A	p.Gly47Ser	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.139G>A	p.Gly47Ser	missense	Exon 1 of 3	ENSP00000248553.6
	HSPB1	ENST00000447574.1	TSL:1	n.164G>A		non_coding_transcript_exon	Exon 1 of 2
	HSPB1	ENST00000676231.2		c.139G>A	p.Gly47Ser	missense	Exon 1 of 4	ENSP00000502249.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000959 AC: 2 AN: 208540 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000630

Gnomad ASJ exome AF: 0.00

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: 0.00000416 AC: 6 AN: 1442672 Hom.: 0 Cov.: 31 AF XY: 0.00000418 AC XY: 3 AN XY: 716980

African (AFR) AF: 0.00 AC: 0 AN: 33252

American (AMR) AF: 0.0000465 AC: 2 AN: 42972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25736

East Asian (EAS) AF: 0.00 AC: 0 AN: 39096

South Asian (SAS) AF: 0.00 AC: 0 AN: 84470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5346

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106578

Other (OTH) AF: 0.0000167 AC: 1 AN: 59708

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000170 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease axonal type 2F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.5
DANN	Benign	0.95
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-1.6	N
PhyloP100		0.14
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.16
Sift	Benign	0.68	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.073
MutPred		0.33		Gain of disorder (P = 0.0581)
MVP		0.57
MPC		0.55
ClinPred		0.048	T
GERP RS		-3.6
PromoterAI		-0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.20
gMVP		0.61
Mutation Taster		=94/6	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

dbSNP: rs778311776; hg19: chr7-75932168;