rs1256690084

Positions:

• chr1-77918017-G-A
• chr1-77918017-G-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.277G>A​(p.Ala93Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NEXN NM_144573.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.86

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=0.25827098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXN	NM_144573.4	c.277G>A	p.Ala93Thr	missense_variant	4/13	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.277G>A	p.Ala93Thr	missense_variant	4/13	1	NM_144573.4	ENSP00000333938	P3
NEXN	ENST00000401035.7	c.85G>A	p.Ala29Thr	missense_variant	3/9	1		ENSP00000383814
NEXN	ENST00000330010.12	c.85G>A	p.Ala29Thr	missense_variant	3/12	2		ENSP00000327363	A1
NEXN	ENST00000440324.5	c.277G>A	p.Ala93Thr	missense_variant	4/10	5		ENSP00000411902

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249400 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135332

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461334 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T;.;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	.;.;L;.
MutationTaster	Benign	0.93	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.14	T;D;D;T
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.63	.;.;P;.
Vest4		0.39, 0.35
MutPred		0.15		.;.;Gain of phosphorylation at A93 (P = 0.0309);Gain of phosphorylation at A93 (P = 0.0309);
MVP		0.82
MPC		0.12
ClinPred		0.43	T
GERP RS		5.8
Varity_R		0.10
gMVP		0.099

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

Publications

LitVar

Other links and lift over

dbSNP: rs1256690084; hg19: chr1-78383702;