chr1-77916039-T-C

Position:

• chr1-77916039-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_144573.4(NEXN):​c.-52-16T>C variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.509

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 -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXN	NM_144573.4	c.-52-16T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.-52-16T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_144573.4	ENSP00000333938	P3
NEXN	ENST00000401035.7	c.-52-16T>C		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000383814
NEXN	ENST00000330010.12	c.-52-16T>C		splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000327363	A1
NEXN	ENST00000440324.5	c.-52-16T>C		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000411902

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

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000106

Gnomad4 FIN exome AF: 0.0000283

Gnomad4 NFE exome AF: 0.000912

Gnomad4 OTH exome AF: 0.000770

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

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000780

Gnomad4 OTH AF: 0.00142

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2014

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs557864364; hg19: chr1-78381724;