6-56620660-C-T

Position:

• chr6-56620660-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001723.7(DST):​c.3374G>A​(p.Arg1125His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1125P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

Genes affected

DST (HGNC:1090): (dystonin) This gene encodes a member of the plakin protein family of adhesion junction plaque proteins. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the full-length nature of some variants has not been defined. It has been reported that some isoforms are expressed in neural and muscle tissue, anchoring neural intermediate filaments to the actin cytoskeleton, and some isoforms are expressed in epithelial tissue, anchoring keratin-containing intermediate filaments to hemidesmosomes. Consistent with the expression, mice defective for this gene show skin blistering and neurodegeneration. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08510113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001723.7	c.3374G>A	p.Arg1125His	missense_variant	23/24	ENST00000370765.11	NP_001714.1
DST	NM_001374736.1	c.4929+3870G>A		intron_variant		ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000370765.11	c.3374G>A	p.Arg1125His	missense_variant	23/24	1	NM_001723.7	ENSP00000359801
DST	ENST00000680361.1	c.4929+3870G>A		intron_variant			NM_001374736.1	ENSP00000505098

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250704 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135496

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461828 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 26, 2019

This sequence change replaces arginine with histidine at codon 1125 of the DST protein (p.Arg1125His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs528372361, ExAC 0.002%). This variant has not been reported in the literature in individuals with DST-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.071
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.010	D
Polyphen		0.0030	B
Vest4		0.30
MutPred		0.28		Loss of MoRF binding (P = 0.0132);
MVP		0.082
ClinPred		0.38	T
GERP RS		2.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs528372361; hg19: chr6-56485458;