rs121908135

Variant names:

• chr1-6452001-G-A
• rs121908135
• NM_031475.3:c.2230G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-6452001-G-A
• chr1-6452001-G-C
• chr1-6452001-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_031475.3(ESPN):​c.2230G>A​(p.Asp744Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,605,250 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:4
• Conservation: PhyloP100: 9.71
• Publications: 7 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3732771).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESPN	NM_031475.3	c.2230G>A	p.Asp744Asn	missense_variant	Exon 10 of 13	ENST00000645284.1	NP_113663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESPN	ENST00000645284.1	c.2230G>A	p.Asp744Asn	missense_variant	Exon 10 of 13		NM_031475.3	ENSP00000496593.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000201 AC: 47 AN: 233842 AF XY: 0.000189

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000394

Gnomad OTH exome AF: 0.000518

GnomAD4 exome AF: 0.000255 AC: 370 AN: 1453094 Hom.: 1 Cov.: 32 AF XY: 0.000259 AC XY: 187 AN XY: 722260

African (AFR) AF: 0.0000300 AC: 1 AN: 33294

American (AMR) AF: 0.0000228 AC: 1 AN: 43906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39334

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.000319 AC: 353 AN: 1107738

Other (OTH) AF: 0.000200 AC: 12 AN: 60046

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74308

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000654 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000206 AC: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Feb 20, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp744Asn variant (rs121908135) was reported in one patient with severe bilateral sensorineural hearing loss, and transfection of this variant in epithelial cell culture resulted in about 10 times higher presence of irregular microvilli patches compared to wild-type (Donaudy 2006). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.04 percent in the European Non-Finnish population (identified on 44 out of 117,486 chromosomes) and has been reported to the ClinVar database (Variation ID: 4421). The aspartic acid at position 744 is highly conserved and computational analyses of the effects of the p.Asp744Asn variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Asp744Asn variant with certainty. -

Aug 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 744 of the ESPN protein (p.Asp744Asn). This variant is present in population databases (rs121908135, gnomAD 0.04%). This missense change has been observed in individual(s) with ESPN-related conditions (PMID: 15930085, 33297549). ClinVar contains an entry for this variant (Variation ID: 4421). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ESPN function (PMID: 15930085). 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. -

Apr 21, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in unrelated individuals with sensorineural hearing loss in published literature (PMID: 15930085, 33297549); 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: 15930085, 33297549) -

Deafness, without vestibular involvement, autosomal dominant Pathogenic:1

Feb 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Autosomal recessive nonsyndromic hearing loss 36;C5231434:Usher syndrome, type 1M Uncertain:1

Mar 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;T;T;T;.;.;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	2.0	M;.;M;.;.;.;.;.
PhyloP100		9.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.0	.;.;D;D;.;.;.;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	.;.;D;D;.;.;.;.
Sift4G	Uncertain	0.020	.;.;D;T;D;.;D;.
Polyphen		1.0	D;.;D;.;D;.;.;.
Vest4		0.56, 0.96, 0.95
MutPred		0.30		Gain of MoRF binding (P = 0.0567);Gain of MoRF binding (P = 0.0567);Gain of MoRF binding (P = 0.0567);.;.;.;.;.;
MVP		0.77
MPC		0.62
ClinPred		0.34	T
GERP RS		5.1
PromoterAI		0.011	Neutral
Varity_R		0.73
gMVP		0.34
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs121908135; hg19: chr1-6512061; COSMIC: COSV64703909; COSMIC: COSV64703909;