1-6444559-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_031475.3(ESPN):c.1069C>T(p.Pro357Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00164 in 1,614,242 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 13 hom., cov: 33)

Exomes 𝑓: 0.00093 ( 11 hom. )

Consequence

ESPN
NM_031475.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.02

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 36
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Usher syndrome type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Usher syndrome, type 1M
Inheritance: AR, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ESPN links:

ENSG00000231868 (HGNC:):

ENSG00000231868 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009067357).

BP6

Variant 1-6444559-C-T is Benign according to our data. Variant chr1-6444559-C-T is described in ClinVar as Benign. ClinVar VariationId is 178607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00848 (1292/152356) while in subpopulation AFR AF = 0.0301 (1251/41580). AF 95% confidence interval is 0.0287. There are 13 homozygotes in GnomAd4. There are 596 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESPN	NM_031475.3 link	c.1069C>T	p.Pro357Ser	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.1069C>T	p.Pro357Ser	missense_variant	Exon 6 of 13		NM_031475.3	ENSP00000496593.1	B1AK53-1
ESPN	ENST00000636330.1 link	c.1069C>T	p.Pro357Ser	missense_variant	Exon 6 of 11	5		ENSP00000490186.1	A0A1B0GUN9
ESPN	ENST00000418286.1 link	c.424C>T	p.Pro142Ser	missense_variant	Exon 4 of 5	3		ENSP00000401793.1	Q5JYL1
ENSG00000231868	ENST00000419034.1 link	n.215+1003G>A		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.00847

AC:

1290

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

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:

0.0000735

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00221

AC:

555

AN:

251456

AF XY:

0.00157

show subpopulations

Gnomad AFR exome

AF:

0.0301

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000930

AC:

1360

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000773

AC XY:

562

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0328

AC:

1098

AN:

33480

American (AMR)

AF:

0.00143

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000809

AC:

AN:

1112008

Other (OTH)

AF:

0.00171

AC:

103

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

101

203

304

406

507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00848

AC:

1292

AN:

152356

Hom.:

Cov.:

AF XY:

0.00800

AC XY:

596

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0301

AC:

1251

AN:

41580

American (AMR)

AF:

0.00176

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68034

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

140

211

281

351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00301

Hom.:

Bravo

AF:

0.0102

ESP6500AA

AF:

0.0268

AC:

118

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00254

AC:

309

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 22, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro357Ser in Exon 06 of ESPN: This variant is not expected to have clinical sign ificance because it has been identified in 2.5% (93/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs116413227). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;T;T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;D;D;D

MetaRNN

Benign

0.0091

T;T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.4

M;.;M;.

PhyloP100

7.0

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.0

.;.;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0040

.;.;D;D

Sift4G

Uncertain

0.027

.;.;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.64

MVP

0.88

MPC

0.64

ClinPred

0.028

GERP RS

3.8

Varity_R

0.35

gMVP

0.64

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over