1-6424956-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_031475.3(ESPN):c.1A>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000853 in 1,288,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: ESPN NM_031475.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Start lost variant, no new inframe start found.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPN	NM_031475.3	c.1A>C	p.Met1?	start_lost	1/13	ENST00000645284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPN	ENST00000645284.1	c.1A>C	p.Met1?	start_lost	1/13		NM_031475.3	P1
ESPN	ENST00000636330.1	c.1A>C	p.Met1?	start_lost	1/11	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000853 AC: 11 AN: 1288914 Hom.: 0 Cov.: 31 AF XY: 0.00000472 AC XY: 3 AN XY: 635350

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000414

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000318

Gnomad4 NFE exome AF: 0.00000775

Gnomad4 OTH exome AF: 0.0000190

GnomAD4 genome Cov.: 33

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

Oct 27, 2021

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. This variant has not been reported in the literature in individuals affected with ESPN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the ESPN mRNA. The next in-frame methionine is located at codon 137. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	23
Dann	Benign	0.92
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	D
Polyphen		0.15	B;.;B
Vest4		0.55
MutPred		0.65		Loss of catalytic residue at M1 (P = 0.2323);Loss of catalytic residue at M1 (P = 0.2323);Loss of catalytic residue at M1 (P = 0.2323);
MVP		0.31
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.87
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6485016;