NM_031475.3:c.28G>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031475.3(ESPN):​c.28G>A​(p.Ala10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A10P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>A	p.Ala10Thr	missense	Exon 1 of 13	NP_113663.2	B1AK53-1
	ESPN	NM_001367474.1		c.28G>A	p.Ala10Thr	missense	Exon 1 of 15	NP_001354403.1
	ESPN	NM_001367473.1		c.28G>A	p.Ala10Thr	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>A	p.Ala10Thr	missense	Exon 1 of 13	ENSP00000496593.1	B1AK53-1
	ESPN	ENST00000636330.1	TSL:5	c.28G>A	p.Ala10Thr	missense	Exon 1 of 11	ENSP00000490186.1	A0A1B0GUN9

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1306198 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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: 0.00 AC: 0 AN: 1042148

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

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151810 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 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: 0.000207 AC: 1 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: 0.00 AC: 0 AN: 67912

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

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.89	P
Vest4		0.32
MutPred		0.45		Gain of phosphorylation at A10 (P = 0.0635)
MVP		0.52
MPC		0.52
ClinPred		0.98	D
GERP RS		2.9
PromoterAI		0.0056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.33
Mutation Taster		=80/20	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;