rs557864364

Variant names:

• chr1-77916039-T-C
• rs557864364
• NM_144573.4:c.-52-16T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-77916039-T-C
• chr1-77916039-T-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_144573.4(NEXN):​c.-52-16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000736 in 955,414 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (1 hom.)
• Consequence: NEXN NM_144573.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.509
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-77916039-T-C is Benign according to our data. Variant chr1-77916039-T-C is described in ClinVar as [Benign]. Clinvar id is 201911.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000487 (74/152046) while in subpopulation AMR AF = 0.000786 (12/15276). AF 95% confidence interval is 0.000612. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4	c.-52-16T>C		intron_variant	Intron 1 of 12	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.-52-16T>C		intron_variant	Intron 1 of 12	1	NM_144573.4	ENSP00000333938.7
NEXN	ENST00000401035.7	c.-52-16T>C		intron_variant	Intron 1 of 8	1		ENSP00000383814.3
NEXN	ENST00000330010.12	c.-52-16T>C		intron_variant	Intron 1 of 11	2		ENSP00000327363.8
NEXN	ENST00000440324.5	c.-52-16T>C		intron_variant	Intron 1 of 9	5		ENSP00000411902.1

Frequencies

GnomAD3 genomes AF: 0.000487 AC: 74 AN: 151932 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000780

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000783 AC: 629 AN: 803368 Hom.: 1 Cov.: 10 AF XY: 0.000808 AC XY: 328 AN XY: 406110

African (AFR) AF: 0.0000602 AC: 1 AN: 16614

American (AMR) AF: 0.00125 AC: 23 AN: 18424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15512

East Asian (EAS) AF: 0.00 AC: 0 AN: 25672

South Asian (SAS) AF: 0.000106 AC: 3 AN: 28248

European-Finnish (FIN) AF: 0.0000283 AC: 1 AN: 35398

Middle Eastern (MID) AF: 0.00122 AC: 3 AN: 2454

European-Non Finnish (NFE) AF: 0.000912 AC: 572 AN: 627260

Other (OTH) AF: 0.000770 AC: 26 AN: 33786

GnomAD4 genome AF: 0.000487 AC: 74 AN: 152046 Hom.: 0 Cov.: 33 AF XY: 0.000377 AC XY: 28 AN XY: 74358

African (AFR) AF: 0.000120 AC: 5 AN: 41524

American (AMR) AF: 0.000786 AC: 12 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000780 AC: 53 AN: 67978

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000774

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 17, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.4
DANN	Benign	0.75
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism

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: rs557864364; hg19: chr1-78381724;