1-77935813-T-G

Variant names:

• chr1-77935813-T-G
• rs201019553
• NM_144573.4:c.1252-10T>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144573.4(NEXN):​c.1252-10T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,608,226 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: NEXN NM_144573.4 intron
• Scores: Splicing: ADA: 0.1620
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.697

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-77935813-T-G is Benign according to our data. Variant chr1-77935813-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 178878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000821 (125/152296) while in subpopulation AFR AF= 0.00289 (120/41568). AF 95% confidence interval is 0.00247. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 125 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4	c.1252-10T>G		intron_variant	Intron 10 of 12	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.1252-10T>G		intron_variant	Intron 10 of 12	1	NM_144573.4	ENSP00000333938.7

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000957

GnomAD3 exomes AF: 0.000199 AC: 49 AN: 246260 Hom.: 0 AF XY: 0.000156 AC XY: 21 AN XY: 134288

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000872 AC: 127 AN: 1455930 Hom.: 0 Cov.: 30 AF XY: 0.0000787 AC XY: 57 AN XY: 724596

Gnomad4 AFR exome AF: 0.00342

Gnomad4 AMR exome AF: 0.0000895

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: 0.00

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74468

Gnomad4 AFR AF: 0.00289

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000532 Hom.: 0

Bravo AF: 0.000941

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Aug 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.1252-10T>G in intron 10 of NEXN: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. I t has been identified in 0.3% (28/8484) of African chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201019553). -

Cardiomyopathy Benign:1

Oct 18, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 29, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NEXN-related disorder Benign:1

Feb 24, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.55
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: rs201019553; hg19: chr1-78401498;