chr1-6441010-C-T

Position:

chr1-6441010-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031475.3(ESPN):c.935C>T(p.Ser312Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000216 in 1,610,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

ESPN
NM_031475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.94

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23882377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESPN	NM_031475.3 linkuse as main transcript	c.935C>T	p.Ser312Leu	missense_variant	5/13	ENST00000645284.1	NP_113663.2	B1AK53-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ESPN	ENST00000645284.1 linkuse as main transcript	c.935C>T	p.Ser312Leu	missense_variant	5/13		NM_031475.3	ENSP00000496593.1	B1AK53-1
ESPN	ENST00000636330.1 linkuse as main transcript	c.935C>T	p.Ser312Leu	missense_variant	5/11	5		ENSP00000490186.1	A0A1B0GUN9
ESPN	ENST00000418286.1 linkuse as main transcript	c.290C>T	p.Ser97Leu	missense_variant	3/5	3		ENSP00000401793.1	Q5JYL1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000121

AC:

AN:

240468

Hom.:

AF XY:

0.000122

AC XY:

AN XY:

131606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000489

Gnomad NFE exome

AF:

0.000250

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.000226

AC:

330

AN:

1458074

Hom.:

Cov.:

AF XY:

0.000211

AC XY:

153

AN XY:

725120

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000899

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000350

Gnomad4 FIN exome

AF:

0.0000769

Gnomad4 NFE exome

AF:

0.000276

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000118

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000213

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000179

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 25, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 449818). This missense change has been observed in individual(s) with deafness (PMID: 30622556). This variant is present in population databases (rs189442618, gnomAD 0.02%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 312 of the ESPN protein (p.Ser312Leu). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2025	Identified in a patient with sensorineural hearing loss in published literature, however, a second ESPN variant was not identified (PMID: 30622556); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17667943, 30622556) -

Autosomal recessive nonsyndromic hearing loss 36

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2018	The ESPN c.935C>T; p.Ser312Leu variant (rs189442618), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 449818). This variant is found in the non-Finnish European population with an overall allele frequency of 0.02% (27/121080 alleles) in the Genome Aggregation Database. The serine at codon 312 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Ser312Leu variant is uncertain at this time. -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T;T;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

.;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.85

L;.;L;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.6

.;.;D;D

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Benign

0.10

.;.;T;D

Polyphen

0.66

P;.;P;.

Vest4

0.58

MVP

0.55

MPC

0.21

ClinPred

0.28

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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