rs727503342

chr1-77917960-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144573.4(NEXN):c.220A>C(p.Ile74Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I74I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEXN NM_144573.4 missense, splice_region
• Scores: Splicing: ADA: 0.9562
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.48

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19512129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXN	NM_144573.4	c.220A>C	p.Ile74Leu	missense_variant, splice_region_variant	4/13	ENST00000334785.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXN	ENST00000334785.12	c.220A>C	p.Ile74Leu	missense_variant, splice_region_variant	4/13	1	NM_144573.4	P3
NEXN	ENST00000401035.7	c.28A>C	p.Ile10Leu	missense_variant, splice_region_variant	3/9	1
NEXN	ENST00000330010.12	c.28A>C	p.Ile10Leu	missense_variant, splice_region_variant	3/12	2		A1
NEXN	ENST00000440324.5	c.220A>C	p.Ile74Leu	missense_variant, splice_region_variant	4/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 24, 2014

The Ile74Leu variant in NEXN has not been previously reported in individuals wit h cardiomyopathy and was absent from large population studies. Isoleucine (Ile) at position 74 is not conserved in evolution and 1 mammal as well as 1 fish spec ies carry a leucine (Leu) at this position, raising the possibility that this ch ange may be tolerated. However, this information is not predictive enough to rul e out pathogenicity. In summary, the clinical significance of the Ile74Leu varia nt is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.016	T;.;T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.25	N;N;N;N
REVEL	Benign	0.094
Sift	Benign	0.040	D;D;D;D
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.27, 0.35
MutPred		0.21		.;.;Loss of methylation at K75 (P = 0.0607);Loss of methylation at K75 (P = 0.0607);
MVP		0.68
MPC		0.047
ClinPred		0.52	D
GERP RS		5.8
Varity_R		0.15
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.96
dbscSNV1_RF	Benign	0.65
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

Publications

LitVar

Other links and lift over

dbSNP: rs727503342; hg19: chr1-78383645;