1-77916133-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_144573.4(NEXN):​c.27G>C​(p.Glu9Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000207 in 1,451,750 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 predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E9E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NEXN NM_144573.4 missense, splice_region
• Scores: Splicing: ADA: 0.9981
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.37

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4	c.27G>C	p.Glu9Asp	missense_variant, splice_region_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>C	p.Glu9Asp	missense_variant, splice_region_variant	Exon 2 of 13	1	NM_144573.4	ENSP00000333938.7
NEXN	ENST00000401035.7	c.27G>C	p.Glu9Asp	missense_variant, splice_region_variant	Exon 2 of 9	1		ENSP00000383814.3
NEXN	ENST00000330010.12	c.27G>C	p.Glu9Asp	missense_variant, splice_region_variant	Exon 2 of 12	2		ENSP00000327363.8
NEXN	ENST00000440324.5	c.27G>C	p.Glu9Asp	missense_variant, splice_region_variant	Exon 2 of 10	5		ENSP00000411902.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451750 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722176

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

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	Uncertain	0.46
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T;.;T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.7	.;M;M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Uncertain	0.050	T;D;D;D
Polyphen		0.99	.;.;D;.
Vest4		0.51, 0.61
MutPred		0.18		Loss of methylation at K7 (P = 0.0984);Loss of methylation at K7 (P = 0.0984);Loss of methylation at K7 (P = 0.0984);Loss of methylation at K7 (P = 0.0984);
MVP		0.83
MPC		0.070
ClinPred		0.91	D
GERP RS		4.6
Varity_R		0.26
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-78381818;