Variant rs727504842 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_031475.3(ESPN):c.2026A>G(p.Thr676Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ESPN
NM_031475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.76

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3472123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESPN	NM_031475.3 linkuse as main transcript	c.2026A>G	p.Thr676Ala	missense_variant	9/13	ENST00000645284.1	NP_113663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESPN	ENST00000645284.1 linkuse as main transcript	c.2026A>G	p.Thr676Ala	missense_variant	9/13		NM_031475.3	ENSP00000496593	P1	B1AK53-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248544

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134970

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:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000205

AC:

AN:

1460610

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 31, 2013

The Thr676Ala variant in ESPN has not been previously reported in individuals wi th hearing loss. Frequency data from large populations studies is insufficient. Computational analyses (biochemical amino acid properties, conservation, AlignGV GD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional data is needed to determine the clinical significance of this variant. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.2026A>G (p.T676A) alteration is located in exon 9 (coding exon 9) of the ESPN gene. This alteration results from a A to G substitution at nucleotide position 2026, causing the threonine (T) at amino acid position 676 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;T;T;T;.;.;T;.;T

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

.;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.35

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

1.8

L;.;L;.;.;.;.;.;.

MutationTaster

Benign

0.65

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.7

.;.;D;D;.;.;.;.;.

REVEL

Uncertain

0.37

Sift

Benign

0.073

.;.;T;T;.;.;.;.;.

Sift4G

Benign

0.16

.;.;T;T;T;.;T;.;.

Polyphen

0.94

P;.;P;.;D;.;.;.;.

Vest4

0.62, 0.73, 0.74

MutPred

0.095

Loss of glycosylation at T676 (P = 0.1162);Loss of glycosylation at T676 (P = 0.1162);Loss of glycosylation at T676 (P = 0.1162);.;.;.;.;.;.;

MVP

0.76

MPC

0.30

ClinPred

0.80

GERP RS

2.5

Varity_R

0.14

gMVP

0.39

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