rs142850918

chr1-6451841-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_031475.3(ESPN):c.2070G>A(p.Ser690=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,611,192 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (46 hom.)
• Consequence: ESPN NM_031475.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.42

Genes affected

ESPN (HGNC:13281): (espin) This gene encodes a multifunctional actin-bundling protein. It plays a major role in regulating the organization, dimensions, dynamics, and signaling capacities of the actin filament-rich, microvillus-type specializations that mediate sensory transduction in various mechanosensory and chemosensory cells. Mutations in this gene are associated with autosomal recessive neurosensory deafness, and autosomal dominant sensorineural deafness without vestibular involvement. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-6451841-G-A is Benign according to our data. Variant chr1-6451841-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6451841-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00497 (757/152304) while in subpopulation NFE AF= 0.0077 (524/68012). AF 95% confidence interval is 0.00716. There are 5 homozygotes in gnomad4. There are 380 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPN	NM_031475.3	c.2070G>A	p.Ser690=	synonymous_variant	10/13	ENST00000645284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPN	ENST00000645284.1	c.2070G>A	p.Ser690=	synonymous_variant	10/13		NM_031475.3	P1

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152186 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00770

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00504 AC: 1225 AN: 242892 Hom.: 6 AF XY: 0.00533 AC XY: 706 AN XY: 132406

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00385

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00280

Gnomad FIN exome AF: 0.00672

Gnomad NFE exome AF: 0.00764

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00618 AC: 9011 AN: 1458888 Hom.: 46 Cov.: 32 AF XY: 0.00614 AC XY: 4455 AN XY: 725574

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00254

Gnomad4 ASJ exome AF: 0.00322

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00249

Gnomad4 FIN exome AF: 0.00656

Gnomad4 NFE exome AF: 0.00705

Gnomad4 OTH exome AF: 0.00559

GnomAD4 genome AF: 0.00497 AC: 757 AN: 152304 Hom.: 5 Cov.: 32 AF XY: 0.00510 AC XY: 380 AN XY: 74474

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00782

Gnomad4 NFE AF: 0.00770

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00689 Hom.: 3

Bravo AF: 0.00466

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ESPN: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 18, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Ser690Ser in Exon 10 of ESPN: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.8% (53/7014) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs142850918). -

Autosomal recessive nonsyndromic hearing loss 36;C5231434:Usher syndrome, type 1M Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 06, 2021

- -

ESPN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2021

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	11
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 35

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142850918; hg19: chr1-6511901;