1-77916133-G-A

Variant names:

• chr1-77916133-G-A
• rs1648957766
• NM_144573.4:c.27G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_144573.4(NEXN):​c.27G>A​(p.Glu9Glu) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000374 in 1,603,630 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NEXN NM_144573.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.8969
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.37
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4	c.27G>A	p.Glu9Glu	splice_region_variant, synonymous_variant	Exon 2 of 13	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.27G>A	p.Glu9Glu	splice_region_variant, synonymous_variant	Exon 2 of 13	1	NM_144573.4	ENSP00000333938.7
NEXN	ENST00000401035.7	c.27G>A	p.Glu9Glu	splice_region_variant, synonymous_variant	Exon 2 of 9	1		ENSP00000383814.3
NEXN	ENST00000330010.12	c.27G>A	p.Glu9Glu	splice_region_variant, synonymous_variant	Exon 2 of 12	2		ENSP00000327363.8
NEXN	ENST00000440324.5	c.27G>A	p.Glu9Glu	splice_region_variant, synonymous_variant	Exon 2 of 10	5		ENSP00000411902.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151880 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1451750 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 722176

African (AFR) AF: 0.00 AC: 0 AN: 33192

American (AMR) AF: 0.00 AC: 0 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25858

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39178

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105830

Other (OTH) AF: 0.00 AC: 0 AN: 59832

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151880 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74162

African (AFR) AF: 0.00 AC: 0 AN: 41322

American (AMR) AF: 0.0000655 AC: 1 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Aug 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.27G>A variant (also known as p.E9E), located in coding exon 1 of the NEXN gene. This variant results from a G to A substitution at nucleotide position 27. This nucleotide substitution does not change the glutamic acid at codon 9. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.89
PhyloP100		6.4
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1648957766; hg19: chr1-78381818;