rs200574474

Variant names:

• chr10-20813941-T-A
• rs200574474
• NM_006393.3:c.2344A>T
• NEBL p.Met782Leu

Your query was ambiguous. Multiple possible variants found:

• chr10-20813941-T-A
• chr10-20813941-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006393.3(NEBL):​c.2344A>T​(p.Met782Leu) variant causes a missense, splice region 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. 14/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M782V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEBL NM_006393.3 missense, splice_region
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.01
• Publications: 5 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.2344A>T	p.Met782Leu	missense splice_region	Exon 23 of 28	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.358-1001A>T		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.358-1001A>T		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.2344A>T	p.Met782Leu	missense splice_region	Exon 23 of 28	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.358-1001A>T		intron	N/A	ENSP00000393896.2	O76041-2
	NEBL	ENST00000493005.5	TSL:1	n.1664A>T		splice_region non_coding_transcript_exon	Exon 10 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-0.0013
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.080
Sift	Benign	0.10	T
Sift4G	Benign	0.29	T
Varity_R		0.27
gMVP		0.21
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
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: rs200574474;

hg19: chr10-21102870;