rs527968078

Positions:

• chr1-6448885-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESPN	NM_031475.3	c.1709C>T	p.Pro570Leu	missense_variant	8/13	ENST00000645284.1	NP_113663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESPN	ENST00000645284.1	c.1709C>T	p.Pro570Leu	missense_variant	8/13		NM_031475.3	ENSP00000496593.1

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

GnomAD3 exomes AF: 0.0139 AC: 391 AN: 28220 Hom.: 8 AF XY: 0.0148 AC XY: 260 AN XY: 17612

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 SAS exome AF: 0.0259

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

Gnomad4 AFR exome AF: 0.00163

Gnomad4 AMR exome AF: 0.0153

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.0271

Gnomad4 SAS exome AF: 0.0214

Gnomad4 FIN exome AF: 0.00965

Gnomad4 NFE exome AF: 0.00402

Gnomad4 OTH exome AF: 0.00653

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

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.0150

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.00480

Gnomad4 OTH AF: 0.00714

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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;T;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.73	.;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;.;N;.
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;.;B;.
Vest4		0.023
MPC		0.15
ClinPred		0.024	T
GERP RS		0.94
Varity_R		0.092
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs527968078; hg19: chr1-6508945; COSMIC: COSV105308065; COSMIC: COSV105308065;