chr5-54456071-G-A

Variant names:

• chr5-54456071-G-A
• rs7699
• NM_006308.3:c.282G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006308.3(HSPB3):​c.282G>A​(p.Leu94Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 1,613,562 control chromosomes in the GnomAD database, including 271,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22442 hom., cov: 30)
  • Exomes 𝑓: 0.58 (248578 hom.)
• Consequence: HSPB3 NM_006308.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.532
• Publications: 20 publications found

Genes affected

HSPB3 (HGNC:5248): (heat shock protein family B (small) member 3) This gene encodes a muscle-specific small heat shock protein. A mutation in this gene is the cause of autosomal dominant distal hereditary motor neuropathy type 2C.[provided by RefSeq, Sep 2010]

HSPB3 Gene-Disease associations (from GenCC):

• distal hereditary motor neuropathy type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neuronopathy, distal hereditary motor, type 2C

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 5-54456071-G-A is Benign according to our data. Variant chr5-54456071-G-A is described in ClinVar as Benign. ClinVar VariationId is 353899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.532 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006308.3. 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
	HSPB3	NM_006308.3	MANE Select	c.282G>A	p.Leu94Leu	synonymous	Exon 1 of 1	NP_006299.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB3	ENST00000302005.3	TSL:6 MANE Select	c.282G>A	p.Leu94Leu	synonymous	Exon 1 of 1	ENSP00000303394.1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81554 AN: 151744 Hom.: 22437 Cov.: 30

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.715

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.659

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.551

GnomAD2 exomes AF: 0.552 AC: 138678 AN: 251306 AF XY: 0.560

Gnomad AFR exome AF: 0.449

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.607

Gnomad EAS exome AF: 0.352

Gnomad FIN exome AF: 0.614

Gnomad NFE exome AF: 0.607

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.580 AC: 848070 AN: 1461700 Hom.: 248578 Cov.: 62 AF XY: 0.581 AC XY: 422144 AN XY: 727168

African (AFR) AF: 0.445 AC: 14914 AN: 33478

American (AMR) AF: 0.459 AC: 20536 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 15721 AN: 26134

East Asian (EAS) AF: 0.345 AC: 13680 AN: 39700

South Asian (SAS) AF: 0.554 AC: 47763 AN: 86254

European-Finnish (FIN) AF: 0.616 AC: 32887 AN: 53418

Middle Eastern (MID) AF: 0.679 AC: 3919 AN: 5768

European-Non Finnish (NFE) AF: 0.597 AC: 663842 AN: 1111834

Other (OTH) AF: 0.576 AC: 34808 AN: 60390

GnomAD4 genome AF: 0.537 AC: 81595 AN: 151862 Hom.: 22442 Cov.: 30 AF XY: 0.534 AC XY: 39611 AN XY: 74196

African (AFR) AF: 0.444 AC: 18374 AN: 41408

American (AMR) AF: 0.475 AC: 7250 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 2097 AN: 3464

East Asian (EAS) AF: 0.355 AC: 1822 AN: 5134

South Asian (SAS) AF: 0.553 AC: 2654 AN: 4796

European-Finnish (FIN) AF: 0.613 AC: 6471 AN: 10556

Middle Eastern (MID) AF: 0.644 AC: 188 AN: 292

European-Non Finnish (NFE) AF: 0.602 AC: 40921 AN: 67930

Other (OTH) AF: 0.555 AC: 1166 AN: 2102

Alfa AF: 0.568 Hom.: 53369

Bravo AF: 0.525

Asia WGS AF: 0.455 AC: 1579 AN: 3478

EpiCase AF: 0.606

EpiControl AF: 0.613

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Neuronopathy, distal hereditary motor, type 2C (4)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		0.53
PromoterAI		-0.076	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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: rs7699; hg19: chr5-53751901; COSMIC: COSV57356747;