rs140734883

Variant names:

• chr10-20897002-A-G
• rs140734883
• NM_006393.3:c.109T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006393.3(NEBL):​c.109T>C​(p.Leu37Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,578 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (10 hom.)
• Consequence: NEBL NM_006393.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.27
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 10-20897002-A-G is Benign according to our data. Variant chr10-20897002-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BS2: High AC in GnomAd4 at 316 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.109T>C	p.Leu37Leu	synonymous	Exon 2 of 28	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.357+64670T>C		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.357+64670T>C		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.109T>C	p.Leu37Leu	synonymous	Exon 2 of 28	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.357+64670T>C		intron	N/A	ENSP00000393896.2	O76041-2
	NEBL	ENST00000863069.1		c.109T>C	p.Leu37Leu	synonymous	Exon 2 of 28	ENSP00000533128.1

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00240 AC: 603 AN: 251430 AF XY: 0.00242

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00182 AC: 2665 AN: 1461310 Hom.: 10 Cov.: 31 AF XY: 0.00184 AC XY: 1339 AN XY: 726966

African (AFR) AF: 0.000358 AC: 12 AN: 33476

American (AMR) AF: 0.00157 AC: 70 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00257 AC: 222 AN: 86252

European-Finnish (FIN) AF: 0.0120 AC: 639 AN: 53198

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.00143 AC: 1586 AN: 1111706

Other (OTH) AF: 0.00133 AC: 80 AN: 60374

GnomAD4 genome AF: 0.00208 AC: 316 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74456

African (AFR) AF: 0.000313 AC: 13 AN: 41572

American (AMR) AF: 0.00209 AC: 32 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.0158 AC: 167 AN: 10590

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00112

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	NEBL-related disorder (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.5
DANN	Benign	0.68
PhyloP100		1.3
PromoterAI		0.021	Neutral
Mutation Taster		=99/1	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: rs140734883; hg19: chr10-21185931;