rs71578983

Variant names:

• chr10-20880791-T-C
• rs71578983
• NM_006393.3:c.480+3A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_006393.3(NEBL):​c.480+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00421 in 1,598,562 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (20 hom.)
• Consequence: NEBL NM_006393.3 splice_region, intron
• Scores: Splicing: ADA: 0.9953
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 4.22
• Publications: 2 publications found

Genes affected

NEBL (HGNC:16932): (nebulette) This gene encodes a nebulin like protein that is abundantly expressed in cardiac muscle. The encoded protein binds actin and interacts with thin filaments and Z-line associated proteins in striated muscle. This protein may be involved in cardiac myofibril assembly. A shorter isoform of this protein termed LIM nebulette is expressed in non-muscle cells and may function as a component of focal adhesion complexes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

NEBL Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

LOC102725112 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 10-20880791-T-C is Benign according to our data. Variant chr10-20880791-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45498.
• BS2: High AC in GnomAd4 at 501 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006393.3. 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
	NEBL	NM_006393.3	MANE Select	c.480+3A>G		splice_region intron	N/A	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.358-67851A>G		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.358-67851A>G		intron	N/A	NP_998734.1	Q59FZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000377122.9	TSL:1 MANE Select	c.480+3A>G		splice_region intron	N/A	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.358-67851A>G		intron	N/A	ENSP00000393896.2	O76041-2
	NEBL	ENST00000863069.1		c.480+3A>G		splice_region intron	N/A	ENSP00000533128.1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00479

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00323 AC: 811 AN: 251352 AF XY: 0.00332

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00591

Gnomad NFE exome AF: 0.00473

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00431 AC: 6235 AN: 1446260 Hom.: 20 Cov.: 29 AF XY: 0.00426 AC XY: 3070 AN XY: 720694

African (AFR) AF: 0.000965 AC: 32 AN: 33152

American (AMR) AF: 0.00116 AC: 52 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00266 AC: 229 AN: 85932

European-Finnish (FIN) AF: 0.00659 AC: 352 AN: 53410

Middle Eastern (MID) AF: 0.000873 AC: 5 AN: 5730

European-Non Finnish (NFE) AF: 0.00489 AC: 5368 AN: 1097814

Other (OTH) AF: 0.00327 AC: 196 AN: 59866

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74480

African (AFR) AF: 0.00103 AC: 43 AN: 41560

American (AMR) AF: 0.00157 AC: 24 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4824

European-Finnish (FIN) AF: 0.00687 AC: 73 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00478 AC: 325 AN: 68034

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00426 Hom.: 4

Bravo AF: 0.00280

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00462

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	1	-	Cardiovascular phenotype (1)
-	-	1	NEBL-related disorder (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		4.2
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.040		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: rs71578983; hg19: chr10-21169720;