chr1-6451841-G-A

Position:

chr1-6451841-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_031475.3(ESPN):c.2070G>A(p.Ser690Ser) 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.42

Variant links:

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]

ESPN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESPN	NM_031475.3 linkuse as main transcript	c.2070G>A	p.Ser690Ser	synonymous_variant	10/13	ENST00000645284.1	NP_113663.2	B1AK53-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESPN	ENST00000645284.1 linkuse as main transcript	c.2070G>A	p.Ser690Ser	synonymous_variant	10/13		NM_031475.3	ENSP00000496593.1		B1AK53-1

Frequencies

GnomAD3 genomes

AF:

0.00499

AC:

759

AN:

152186

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00533

AC XY:

706

AN XY:

132406

show subpopulations

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.:

Cov.:

AF XY:

0.00614

AC XY:

4455

AN XY:

725574

show subpopulations

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.:

Cov.:

AF XY:

0.00510

AC XY:

380

AN XY:

74474

show subpopulations

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.:

Bravo

AF:

0.00466

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ESPN: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

not specified

Benign:2

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). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2020	- -

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, no assertion criteria provided

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over