rs527968078

Variant names:

• chr1-6448885-C-T
• rs527968078
• NM_031475.3:c.1709C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.552
• Publications: 2 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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.: 8 Cov.: 33

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

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.: 60 Cov.: 31 AF XY: 0.00622 AC XY: 3552 AN XY: 570652

African (AFR) AF: 0.00163 AC: 38 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: 67 AN: 3248

European-Non Finnish (NFE) AF: 0.00402 AC: 3916 AN: 975052

Other (OTH) AF: 0.00653 AC: 309 AN: 47306

GnomAD4 genome AF: 0.00601 AC: 912 AN: 151670 Hom.: 8 Cov.: 33 AF XY: 0.00651 AC XY: 483 AN XY: 74146

African (AFR) AF: 0.00104 AC: 43 AN: 41500

American (AMR) AF: 0.0122 AC: 186 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3466

East Asian (EAS) AF: 0.0150 AC: 77 AN: 5150

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4830

European-Finnish (FIN) AF: 0.0118 AC: 122 AN: 10376

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.00480 AC: 326 AN: 67848

Other (OTH) AF: 0.00714 AC: 15 AN: 2100

Alfa AF: 0.00598 Hom.: 0

Bravo AF: 0.00546

ExAC AF: 0.0137 AC: 174

Asia WGS AF: 0.0150 AC: 49 AN: 3308

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.55
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.036
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.0	B
Vest4		0.023
MPC		0.15
ClinPred		0.024	T
GERP RS		0.94
PromoterAI		0.038	Neutral
Varity_R		0.092
gMVP		0.14
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs527968078; hg19: chr1-6508945;