Genetic Variant NM_031475.3:c.1709C>T (chr1-6448885-C-T) – ACMG Classification: Benign (-20 pts)

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.1709C>T(p.Pro570Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00573 in 1,325,674 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P570S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0060 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0057 ( 60 hom. )

Consequence

ESPN
NM_031475.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.552

Publications

2 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:

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=0.002673477).

BP6

Variant 1-6448885-C-T is Benign according to our data. Variant chr1-6448885-C-T is described in ClinVar as Benign. ClinVar VariationId is 445819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00601 (912/151670) while in subpopulation SAS AF = 0.0174 (84/4830). AF 95% confidence interval is 0.0144. There are 8 homozygotes in GnomAd4. There are 483 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ESPN	NM_031475.3	MANE Select	c.1709C>T	p.Pro570Leu	missense	Exon 8 of 13	NP_113663.2
ESPN	NM_001367474.1		c.1627-8C>T		splice_region intron	N/A	NP_001354403.1
ESPN	NM_001367473.1		c.1627-8C>T		splice_region intron	N/A	NP_001354402.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ESPN	ENST00000645284.1	MANE Select	c.1709C>T	p.Pro570Leu	missense	Exon 8 of 13	ENSP00000496593.1
ESPN	ENST00000461727.6	TSL:1	c.19-8C>T		splice_region intron	N/A	ENSP00000465308.1
ESPN	ENST00000636330.1	TSL:5	c.1709C>T	p.Pro570Leu	missense	Exon 8 of 11	ENSP00000490186.1

Frequencies

GnomAD3 genomes

AF:

0.00602

AC:

913

AN:

151562

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.0151

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.00480

Gnomad OTH

AF:

0.00722

GnomAD2 exomes

AF:

0.0139

AC:

391

AN:

28220

AF XY:

0.0148

show subpopulations

Gnomad AFR exome

AF:

0.00259

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.0186

Gnomad EAS exome

AF:

0.0148

Gnomad FIN exome

AF:

0.0112

Gnomad NFE exome

AF:

0.00567

Gnomad OTH exome

AF:

0.0136

GnomAD4 exome

AF:

0.00569

AC:

6679

AN:

1174004

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

3552

AN XY:

570652

show subpopulations

African (AFR)

AF:

0.00163

AC:

AN:

23354

American (AMR)

AF:

0.0153

AC:

184

AN:

11996

Ashkenazi Jewish (ASJ)

AF:

0.0166

AC:

280

AN:

16826

East Asian (EAS)

AF:

0.0271

AC:

692

AN:

25574

South Asian (SAS)

AF:

0.0214

AC:

932

AN:

43600

European-Finnish (FIN)

AF:

0.00965

AC:

261

AN:

27048

Middle Eastern (MID)

AF:

0.0206

AC:

AN:

3248

European-Non Finnish (NFE)

AF:

0.00402

AC:

3916

AN:

975052

Other (OTH)

AF:

0.00653

AC:

309

AN:

47306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

365

730

1094

1459

1824

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

170

340

510

680

850

<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:

0.00601

AC:

912

AN:

151670

Hom.:

Cov.:

AF XY:

0.00651

AC XY:

483

AN XY:

74146

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

41500

American (AMR)

AF:

0.0122

AC:

186

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3466

East Asian (EAS)

AF:

0.0150

AC:

AN:

5150

South Asian (SAS)

AF:

0.0174

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0118

AC:

122

AN:

10376

Middle Eastern (MID)

AF:

0.0240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00480

AC:

326

AN:

67848

Other (OTH)

AF:

0.00714

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

139

186

232

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:

0.00598

Hom.:

Bravo

AF:

0.00546

ExAC

AF:

0.0137

AC:

174

Asia WGS

AF:

0.0150

AC:

AN:

3308

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

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

May 15, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.050

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

-0.55

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.31

REVEL

Benign

0.036

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.0

Vest4

0.023

MPC

0.15

ClinPred

0.024

GERP RS

0.94

PromoterAI

0.038

Neutral

(source)

Varity_R

0.092

gMVP

0.14

Mutation Taster

=85/15

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over