rs143645714

Positions:

Variant summary

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

The NM_031475.3(ESPN):c.1049C>G(p.Pro350Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,614,226 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P350S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 4 hom. )

Consequence

ESPN
NM_031475.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.72

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:

(HGNC:):

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=0.008527875).

BP6

Variant 1-6444539-C-G is Benign according to our data. Variant chr1-6444539-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 227356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6444539-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000151 (23/152340) while in subpopulation SAS AF= 0.00393 (19/4834). AF 95% confidence interval is 0.00257. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPN	NM_031475.3 linkuse as main transcript	c.1049C>G	p.Pro350Arg	missense_variant	6/13	ENST00000645284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPN	ENST00000645284.1 linkuse as main transcript	c.1049C>G	p.Pro350Arg	missense_variant	6/13		NM_031475.3	P1	B1AK53-1
	ENST00000419034.1 linkuse as main transcript	n.215+1023G>C		intron_variant, non_coding_transcript_variant		5
ESPN	ENST00000636330.1 linkuse as main transcript	c.1049C>G	p.Pro350Arg	missense_variant	6/11	5
ESPN	ENST00000418286.1 linkuse as main transcript	c.404C>G	p.Pro135Arg	missense_variant	4/5	3

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000533

AC:

134

AN:

251428

Hom.:

AF XY:

0.000692

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00382

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000239

AC:

349

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

234

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00342

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000151

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000610

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 26, 2016	p.Pro350Arg in Exon 6 of ESPN: This variant is not expected to have clinical sig nificance because it has been identified in 0.39% (64/16512) of South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs143645714) -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.22

T;T;T;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.71

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.87

.;D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.0085

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;M;.

MutationTaster

Benign

0.90

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.4

.;.;D;D

REVEL

Benign

0.16

Sift

Benign

0.40

.;.;T;T

Sift4G

Benign

0.45

.;.;T;T

Polyphen

0.98

D;.;D;.

Vest4

0.59

MVP

0.20

MPC

0.59

ClinPred

0.098

GERP RS

0.73

Varity_R

0.049

gMVP

0.45

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