1-6425172-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_031475.3(ESPN):c.217C>G(p.Pro73Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,380,172 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: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (1 hom.)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3532652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPN	NM_031475.3	c.217C>G	p.Pro73Ala	missense_variant	1/13	ENST00000645284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPN	ENST00000645284.1	c.217C>G	p.Pro73Ala	missense_variant	1/13		NM_031475.3	P1
ESPN	ENST00000636330.1	c.217C>G	p.Pro73Ala	missense_variant	1/11	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000307 AC: 4 AN: 130278 Hom.: 0 AF XY: 0.0000418 AC XY: 3 AN XY: 71728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000178

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 19 AN: 1380172 Hom.: 1 Cov.: 31 AF XY: 0.0000191 AC XY: 13 AN XY: 681478

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.000190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000110 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 73 of the ESPN protein (p.Pro73Ala). This variant is present in population databases (rs759497805, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ESPN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1402536). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.23	N;.;N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
Polyphen		1.0	D;.;D
Vest4		0.33
MutPred		0.39		Loss of phosphorylation at T72 (P = 0.0893);Loss of phosphorylation at T72 (P = 0.0893);Loss of phosphorylation at T72 (P = 0.0893);
MVP		0.63
MPC		0.59
ClinPred		0.64	D
GERP RS		4.0
Varity_R		0.41
gMVP		0.36

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

Other links and lift over

dbSNP: rs759497805; hg19: chr1-6485232;