chr6-7542041-T-C

Variant names:

• chr6-7542041-T-C
• rs36087964
• NM_004415.4:c.126T>C

Variant summary

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

The NM_004415.4(DSP):​c.126T>C​(p.Tyr42Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,575,704 control chromosomes in the GnomAD database, including 2,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (425 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2333 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 1.70
• Publications: 10 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 6-7542041-T-C is Benign according to our data. Variant chr6-7542041-T-C is described in ClinVar as Benign. ClinVar VariationId is 44855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0999 is higher than 0.05.

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.126T>C	p.Tyr42Tyr	synonymous	Exon 1 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.126T>C	p.Tyr42Tyr	synonymous	Exon 1 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.126T>C	p.Tyr42Tyr	synonymous	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.126T>C	p.Tyr42Tyr	synonymous	Exon 1 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.126T>C	p.Tyr42Tyr	synonymous	Exon 1 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000710359.2		c.126T>C	p.Tyr42Tyr	synonymous	Exon 1 of 24	ENSP00000518230.1	P15924-3

Frequencies

GnomAD3 genomes AF: 0.0678 AC: 10307 AN: 151964 Hom.: 418 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0427

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0545

Gnomad OTH AF: 0.0680

GnomAD2 exomes AF: 0.0546 AC: 9906 AN: 181368 AF XY: 0.0550

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.0166

Gnomad FIN exome AF: 0.0605

Gnomad NFE exome AF: 0.0555

Gnomad OTH exome AF: 0.0685

GnomAD4 exome AF: 0.0558 AC: 79432 AN: 1423620 Hom.: 2333 Cov.: 32 AF XY: 0.0556 AC XY: 39164 AN XY: 704802

African (AFR) AF: 0.104 AC: 3389 AN: 32576

American (AMR) AF: 0.0359 AC: 1411 AN: 39344

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2763 AN: 25432

East Asian (EAS) AF: 0.0417 AC: 1565 AN: 37528

South Asian (SAS) AF: 0.0496 AC: 4034 AN: 81366

European-Finnish (FIN) AF: 0.0613 AC: 3024 AN: 49346

Middle Eastern (MID) AF: 0.0930 AC: 532 AN: 5722

European-Non Finnish (NFE) AF: 0.0539 AC: 58953 AN: 1093368

Other (OTH) AF: 0.0638 AC: 3761 AN: 58938

GnomAD4 genome AF: 0.0680 AC: 10344 AN: 152084 Hom.: 425 Cov.: 33 AF XY: 0.0674 AC XY: 5013 AN XY: 74382

African (AFR) AF: 0.103 AC: 4254 AN: 41502

American (AMR) AF: 0.0471 AC: 721 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 368 AN: 3466

East Asian (EAS) AF: 0.0261 AC: 134 AN: 5142

South Asian (SAS) AF: 0.0434 AC: 209 AN: 4818

European-Finnish (FIN) AF: 0.0585 AC: 620 AN: 10592

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0546 AC: 3707 AN: 67954

Other (OTH) AF: 0.0678 AC: 143 AN: 2110

Alfa AF: 0.0605 Hom.: 547

Bravo AF: 0.0696

Asia WGS AF: 0.0460 AC: 160 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Cardiomyopathy (2)
-	-	1	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8 (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lethal acantholytic epidermolysis bullosa (1)
-	-	1	not provided (1)
-	-	1	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		1.7
PromoterAI		0.030	Neutral
Mutation Taster		=95/5	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: rs36087964; hg19: chr6-7542274;