1-77916097-T-C

Variant names:

• chr1-77916097-T-C
• rs727505219
• NM_144573.4:c.-10T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_144573.4(NEXN):​c.-10T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,604,986 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: NEXN NM_144573.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.79
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4	c.-10T>C		5_prime_UTR_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.-10T>C		5_prime_UTR_variant	Exon 2 of 13	1	NM_144573.4	ENSP00000333938.7
NEXN	ENST00000401035.7	c.-10T>C		5_prime_UTR_variant	Exon 2 of 9	1		ENSP00000383814.3
NEXN	ENST00000330010.12	c.-10T>C		5_prime_UTR_variant	Exon 2 of 12	2		ENSP00000327363.8
NEXN	ENST00000440324.5	c.-10T>C		5_prime_UTR_variant	Exon 2 of 10	5		ENSP00000411902.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151914 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000404 AC: 1 AN: 247630 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453072 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723020

African (AFR) AF: 0.0000301 AC: 1 AN: 33264

American (AMR) AF: 0.00 AC: 0 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39206

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5394

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106844

Other (OTH) AF: 0.00 AC: 0 AN: 59830

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151914 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74198

African (AFR) AF: 0.0000725 AC: 3 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.32
DANN	Benign	0.70
PhyloP100		-2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727505219; hg19: chr1-78381782;