rs77445784

Variant names:

• chr6-7542020-G-A
• rs77445784
• NM_004415.4:c.105G>A
• DSP p.Gly35Gly

Your query was ambiguous. Multiple possible variants found:

• chr6-7542020-G-A
• chr6-7542020-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004415.4(DSP):​c.105G>A​(p.Gly35Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00785 in 1,584,904 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (58 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -0.489
• Publications: 1 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=-0.5).
• BP6: Variant 6-7542020-G-A is Benign according to our data. Variant chr6-7542020-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.489 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00575 (876/152312) while in subpopulation AMR AF = 0.0106 (163/15308). AF 95% confidence interval is 0.00931. There are 4 homozygotes in GnomAd4. There are 405 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.105G>A	p.Gly35Gly	synonymous	Exon 1 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.105G>A	p.Gly35Gly	synonymous	Exon 1 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.105G>A	p.Gly35Gly	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.105G>A	p.Gly35Gly	synonymous	Exon 1 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.105G>A	p.Gly35Gly	synonymous	Exon 1 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000710359.2		c.105G>A	p.Gly35Gly	synonymous	Exon 1 of 24	ENSP00000518230.1	P15924-3

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 877 AN: 152194 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00530 AC: 1010 AN: 190676 AF XY: 0.00528

Gnomad AFR exome AF: 0.00211

Gnomad AMR exome AF: 0.00493

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00179

Gnomad NFE exome AF: 0.00939

Gnomad OTH exome AF: 0.00707

GnomAD4 exome AF: 0.00807 AC: 11562 AN: 1432592 Hom.: 58 Cov.: 32 AF XY: 0.00777 AC XY: 5521 AN XY: 710218

African (AFR) AF: 0.00177 AC: 58 AN: 32842

American (AMR) AF: 0.00536 AC: 218 AN: 40654

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 40 AN: 25552

East Asian (EAS) AF: 0.00 AC: 0 AN: 38070

South Asian (SAS) AF: 0.000730 AC: 60 AN: 82178

European-Finnish (FIN) AF: 0.00257 AC: 128 AN: 49808

Middle Eastern (MID) AF: 0.00436 AC: 25 AN: 5738

European-Non Finnish (NFE) AF: 0.00963 AC: 10581 AN: 1098502

Other (OTH) AF: 0.00763 AC: 452 AN: 59248

GnomAD4 genome AF: 0.00575 AC: 876 AN: 152312 Hom.: 4 Cov.: 33 AF XY: 0.00544 AC XY: 405 AN XY: 74480

African (AFR) AF: 0.00176 AC: 73 AN: 41582

American (AMR) AF: 0.0106 AC: 163 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00870 AC: 592 AN: 68012

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00558 Hom.: 0

Bravo AF: 0.00645

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	not provided (4)
-	-	2	Cardiomyopathy (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 8 (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Lethal acantholytic epidermolysis bullosa (1)
-	-	1	Woolly hair-skin fragility syndrome (1)
-	-	1	Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.7
DANN	Benign	0.96
PhyloP100		-0.49
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=98/2	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

dbSNP: rs77445784;

hg19: chr6-7542253;