chr7-76302890-C-A

Variant names:

• chr7-76302890-C-A
• rs61751217
• NM_001540.5:c.178C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001540.5(HSPB1):​c.178C>A​(p.Pro60Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,206 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P60R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.134
• 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: Uncertain_significance. The variant received 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.16138268).

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.178C>A	p.Pro60Thr	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.178C>A	p.Pro60Thr	missense	Exon 1 of 3	ENSP00000248553.6
	HSPB1	ENST00000447574.1	TSL:1	n.203C>A		non_coding_transcript_exon	Exon 1 of 2
	HSPB1	ENST00000676231.2		c.178C>A	p.Pro60Thr	missense	Exon 1 of 4	ENSP00000502249.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408206 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 697214

African (AFR) AF: 0.00 AC: 0 AN: 32486

American (AMR) AF: 0.00 AC: 0 AN: 38502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 37332

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5090

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090822

Other (OTH) AF: 0.00 AC: 0 AN: 58558

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.9
DANN	Benign	0.90
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.94	L
PhyloP100		-0.13
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.19
Sift	Benign	0.23	T
Sift4G	Benign	0.31	T
Polyphen		0.0040	B
Vest4		0.061
MutPred		0.33		Loss of catalytic residue at P59 (P = 0.0219)
MVP		0.77
MPC		0.62
ClinPred		0.057	T
GERP RS		-3.6
PromoterAI		-0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.033
gMVP		0.52
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

dbSNP: rs61751217; hg19: chr7-75932207;