rs934411593

Variant names:

• chr1-6424983-G-C
• rs934411593
• NM_031475.3:c.28G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-6424983-G-C
• chr1-6424983-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_031475.3(ESPN):​c.28G>C​(p.Ala10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,458,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10
• Publications: 0 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):

• autosomal recessive nonsyndromic hearing loss 36

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• 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: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	NM_031475.3	MANE Select	c.28G>C	p.Ala10Pro	missense	Exon 1 of 13	NP_113663.2	B1AK53-1
	ESPN	NM_001367474.1		c.28G>C	p.Ala10Pro	missense	Exon 1 of 15	NP_001354403.1
	ESPN	NM_001367473.1		c.28G>C	p.Ala10Pro	missense	Exon 1 of 14	NP_001354402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	ENST00000645284.1	MANE Select	c.28G>C	p.Ala10Pro	missense	Exon 1 of 13	ENSP00000496593.1	B1AK53-1
	ESPN	ENST00000636330.1	TSL:5	c.28G>C	p.Ala10Pro	missense	Exon 1 of 11	ENSP00000490186.1	A0A1B0GUN9

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151810 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000995 AC: 13 AN: 1306198 Hom.: 0 Cov.: 31 AF XY: 0.00000932 AC XY: 6 AN XY: 643866

African (AFR) AF: 0.00 AC: 0 AN: 26194

American (AMR) AF: 0.00 AC: 0 AN: 25294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22648

East Asian (EAS) AF: 0.00 AC: 0 AN: 27606

South Asian (SAS) AF: 0.00 AC: 0 AN: 72102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3844

European-Non Finnish (NFE) AF: 0.0000125 AC: 13 AN: 1042148

Other (OTH) AF: 0.00 AC: 0 AN: 53768

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151810 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74150

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67912

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.0031
Eigen_PC	Benign	-0.0059
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	4.4	H
PhyloP100		2.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.10	B
Vest4		0.64
MutPred		0.47		Loss of stability (P = 0.103)
MVP		0.47
MPC		0.68
ClinPred		1.0	D
GERP RS		2.9
PromoterAI		0.0088	Neutral
Varity_R		0.81
gMVP		0.74
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs934411593; hg19: chr1-6485043;