chr1-77916044-AT-A

Variant names:

• chr1-77916044-AT-A
• rs972673849
• NM_144573.4:c.-52-4delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_144573.4(NEXN):​c.-52-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000463 in 1,102,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: NEXN NM_144573.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.282
• 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 -10 ACMG points.

• BP6: Variant 1-77916044-AT-A is Benign according to our data. Variant chr1-77916044-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 518082.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000105 (16/151976) while in subpopulation AFR AF = 0.000362 (15/41410). AF 95% confidence interval is 0.000222. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4	c.-52-4delT		splice_region_variant, 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.-52-10delT		intron_variant	Intron 1 of 12	1	NM_144573.4	ENSP00000333938.7
NEXN	ENST00000401035.7	c.-52-10delT		intron_variant	Intron 1 of 8	1		ENSP00000383814.3
NEXN	ENST00000330010.12	c.-52-10delT		intron_variant	Intron 1 of 11	2		ENSP00000327363.8
NEXN	ENST00000440324.5	c.-52-10delT		intron_variant	Intron 1 of 9	5		ENSP00000411902.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151976 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD4 exome AF: 0.0000368 AC: 35 AN: 950352 Hom.: 0 Cov.: 12 AF XY: 0.0000379 AC XY: 18 AN XY: 475094

African (AFR) AF: 0.000458 AC: 9 AN: 19652

American (AMR) AF: 0.00 AC: 0 AN: 20726

Ashkenazi Jewish (ASJ) AF: 0.0000594 AC: 1 AN: 16828

East Asian (EAS) AF: 0.00 AC: 0 AN: 27832

South Asian (SAS) AF: 0.0000933 AC: 3 AN: 32156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2806

European-Non Finnish (NFE) AF: 0.0000225 AC: 17 AN: 754290

Other (OTH) AF: 0.000129 AC: 5 AN: 38752

GnomAD4 genome AF: 0.000105 AC: 16 AN: 151976 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74236

African (AFR) AF: 0.000362 AC: 15 AN: 41410

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000110

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 13, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs972673849; hg19: chr1-78381729;