10-21173769-T-A

Variant names:

• chr10-21173769-T-A
• rs727503341
• ENST00000417816.2:c.65A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001377322.1(NEBL):​c.65A>T​(p.Asp22Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEBL NM_001377322.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.81
• Publications: 0 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-AS1 (HGNC:44899): (NEBL antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377322.1. 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_001377322.1		c.65A>T	p.Asp22Val	missense	Exon 1 of 8	NP_001364251.1
	NEBL	NM_213569.2		c.65A>T	p.Asp22Val	missense	Exon 1 of 7	NP_998734.1	Q59FZ8
	NEBL	NM_001173484.2		c.65A>T	p.Asp22Val	missense	Exon 1 of 7	NP_001166955.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000417816.2	TSL:1	c.65A>T	p.Asp22Val	missense	Exon 1 of 7	ENSP00000393896.2	O76041-2
	NEBL	ENST00000464278.1	TSL:3	n.70A>T		non_coding_transcript_exon	Exon 1 of 2
	NEBL	ENST00000675747.1		n.125A>T		non_coding_transcript_exon	Exon 1 of 28

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Benign	0.97
Eigen	Benign	0.13
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.22	D
PhyloP100		4.8
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.053	T
Vest4		0.69
MutPred		0.60		Gain of methylation at K23 (P = 0.0292)
MVP		0.83
ClinPred		0.98	D
GERP RS		1.8
PromoterAI		-0.048	Neutral
Mutation Taster		=85/15	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: rs727503341; hg19: chr10-21462698;