rs367871780

Variant names:

• chr1-77917982-A-T
• rs367871780
• NM_144573.4:c.242A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BS1 BS2

The NM_144573.4(NEXN):​c.242A>T​(p.Asp81Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,613,170 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: NEXN NM_144573.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 8.52
• Publications: 1 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: STRONG 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: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3014954).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000236 (36/152246) while in subpopulation AFR AF = 0.000844 (35/41470). AF 95% confidence interval is 0.000623. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 36 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144573.4. 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
	NEXN	NM_144573.4	MANE Select	c.242A>T	p.Asp81Val	missense	Exon 4 of 13	NP_653174.3	Q0ZGT2-1
	NEXN	NM_001172309.2		c.50A>T	p.Asp17Val	missense	Exon 3 of 12	NP_001165780.1	Q0ZGT2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXN	ENST00000334785.12	TSL:1 MANE Select	c.242A>T	p.Asp81Val	missense	Exon 4 of 13	ENSP00000333938.7	Q0ZGT2-1
	NEXN	ENST00000401035.7	TSL:1	c.50A>T	p.Asp17Val	missense	Exon 3 of 9	ENSP00000383814.3	E7ETM8
	NEXN	ENST00000951152.1		c.242A>T	p.Asp81Val	missense	Exon 5 of 14	ENSP00000621211.1

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000844

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

GnomAD2 exomes AF: 0.0000361 AC: 9 AN: 249346 AF XY: 0.0000296

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460924 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 726804

African (AFR) AF: 0.000897 AC: 30 AN: 33450

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111496

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74382

African (AFR) AF: 0.000844 AC: 35 AN: 41470

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.000828 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Cardiovascular phenotype (2)
-	1	-	Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 (1)
-	1	-	Left ventricular hypertrophy (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.88
MPC		0.24
ClinPred		0.27	T
GERP RS		5.7
PromoterAI		-0.018	Neutral
Varity_R		0.30
gMVP		0.14
Mutation Taster		=41/59	disease causing

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: rs367871780; hg19: chr1-78383667;