rs878855209

Variant names:

• chr1-77933317-A-C
• rs878855209
• NM_144573.4:c.1089A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_144573.4(NEXN):​c.1089A>C​(p.Thr363Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NEXN NM_144573.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.58
• Publications: 0 publications found

Genes affected

NEXN (HGNC:29557): (nexilin F-actin binding protein) This gene encodes a filamentous actin-binding protein that may function in cell adhesion and migration. Mutations in this gene have been associated with dilated cardiomyopathy, also known as CMD1CC. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

NEXN Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1CC

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy 20

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.107).
• BP6: Variant 1-77933317-A-C is Benign according to our data. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-77933317-A-C is described in CliVar as Likely_benign. Clinvar id is 241864.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.58 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4	c.1089A>C	p.Thr363Thr	synonymous_variant	Exon 10 of 13	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.1089A>C	p.Thr363Thr	synonymous_variant	Exon 10 of 13	1	NM_144573.4	ENSP00000333938.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454130 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723676

African (AFR) AF: 0.00 AC: 0 AN: 33216

American (AMR) AF: 0.00 AC: 0 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 85596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5546

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106188

Other (OTH) AF: 0.00 AC: 0 AN: 60052

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Benign:1

May 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.4
DANN	Benign	0.51
PhyloP100		2.6
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: rs878855209; hg19: chr1-78399002;