6-7541927-C-A

Variant names:

• chr6-7541927-C-A
• NM_004415.4:c.12C>A
• DSP p.Asn4Lys

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004415.4(DSP):​c.12C>A​(p.Asn4Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N4S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.129
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25606948).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.12C>A	p.Asn4Lys	missense	Exon 1 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.12C>A	p.Asn4Lys	missense	Exon 1 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.12C>A	p.Asn4Lys	missense	Exon 1 of 24	NP_001008844.1	P15924-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.12C>A	p.Asn4Lys	missense	Exon 1 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.12C>A	p.Asn4Lys	missense	Exon 1 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000710359.2		c.12C>A	p.Asn4Lys	missense	Exon 1 of 24	ENSP00000518230.1	P15924-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.096
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.13
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.11
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.20
gMVP		0.65
Mutation Taster		=96/4	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-7542160;