6-7541962-G-T

Variant names:

• chr6-7541962-G-T
• rs752387234
• NM_004415.4:c.47G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004415.4(DSP):​c.47G>T​(p.Arg16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R16C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• Publications: 0 publications found

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DSP-AS1 (HGNC:56039): (DSP antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004415.4. 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
	DSP	NM_004415.4	MANE Select	c.47G>T	p.Arg16Leu	missense	Exon 1 of 24	NP_004406.2
	DSP	NM_001319034.2		c.47G>T	p.Arg16Leu	missense	Exon 1 of 24	NP_001305963.1
	DSP	NM_001008844.3		c.47G>T	p.Arg16Leu	missense	Exon 1 of 24	NP_001008844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.47G>T	p.Arg16Leu	missense	Exon 1 of 24	ENSP00000369129.3
	DSP	ENST00000418664.3	TSL:1	c.47G>T	p.Arg16Leu	missense	Exon 1 of 24	ENSP00000396591.2
	DSP	ENST00000710359.2		c.47G>T	p.Arg16Leu	missense	Exon 1 of 24	ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000879 AC: 2 AN: 227516 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000105

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: 6.87e-7 AC: 1 AN: 1455014 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723288

African (AFR) AF: 0.00 AC: 0 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 44172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39440

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109852

Other (OTH) AF: 0.00 AC: 0 AN: 60038

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.53
MutPred		0.39		Loss of MoRF binding (P = 0.0018)
MVP		0.87
MPC		0.31
ClinPred		0.61	D
GERP RS		3.7
PromoterAI		0.096	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.70
Mutation Taster		=62/38	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: rs752387234; hg19: chr6-7542195;