rs142638391

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_031475.3(ESPN):c.1104T>G(p.Phe368Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 1,614,218 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 4 hom. )

Consequence

ESPN
NM_031475.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.206

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:

ENSG00000231868 (HGNC:):

ENSG00000231868 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008469462).

BP6

Variant 1-6444594-T-G is Benign according to our data. Variant chr1-6444594-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 163413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6444594-T-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00381 (581/152332) while in subpopulation AFR AF= 0.0134 (557/41580). AF 95% confidence interval is 0.0125. There are 3 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESPN	NM_031475.3 link	c.1104T>G	p.Phe368Leu	missense_variant	Exon 6 of 13	ENST00000645284.1	NP_113663.2	B1AK53-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ESPN	ENST00000645284.1 link	c.1104T>G	p.Phe368Leu	missense_variant	Exon 6 of 13		NM_031475.3	ENSP00000496593.1	B1AK53-1
ESPN	ENST00000636330.1 link	c.1104T>G	p.Phe368Leu	missense_variant	Exon 6 of 11	5		ENSP00000490186.1	A0A1B0GUN9
ESPN	ENST00000418286.1 link	c.459T>G	p.Phe153Leu	missense_variant	Exon 4 of 5	3		ENSP00000401793.1	Q5JYL1
ENSG00000231868	ENST00000419034.1 link	n.215+968A>C		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.00380

AC:

579

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.000103

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000946

AC:

238

AN:

251474

Hom.:

AF XY:

0.000596

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.000781

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:

0.0000176

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000319

AC:

467

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000259

AC XY:

188

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0111

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.00381

AC:

581

AN:

152332

Hom.:

Cov.:

AF XY:

0.00358

AC XY:

267

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0134

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.00409

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Phe368Leu in Exon 06 of ESPN: This variant is not expected to have clinical sign ificance because it has been identified in 1.0% (36/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs142638391). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.61

.;T;T;T

MetaRNN

Benign

0.0085

T;T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.4

M;.;M;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.1

.;.;D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.026

.;.;D;T

Sift4G

Benign

0.12

.;.;T;D

Polyphen

1.0

D;.;D;.

Vest4

0.37

MutPred

0.40

Gain of glycosylation at S372 (P = 0.1045);Gain of glycosylation at S372 (P = 0.1045);Gain of glycosylation at S372 (P = 0.1045);.;

MVP

0.79

MPC

0.17

ClinPred

0.054

GERP RS

-1.3

Varity_R

0.22

gMVP

0.55

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

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