rs1024918977

Variant names:

• chr1-6425058-C-T
• rs1024918977
• NM_031475.3:c.103C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_031475.3(ESPN):​c.103C>T​(p.Leu35Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,471,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: ESPN NM_031475.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.895
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-6425058-C-T is Benign according to our data. Variant chr1-6425058-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3670875.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.895 with no splicing effect.

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.103C>T	p.Leu35Leu	synonymous	Exon 1 of 13	NP_113663.2	B1AK53-1
	ESPN	NM_001367474.1		c.103C>T	p.Leu35Leu	synonymous	Exon 1 of 15	NP_001354403.1
	ESPN	NM_001367473.1		c.103C>T	p.Leu35Leu	synonymous	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.103C>T	p.Leu35Leu	synonymous	Exon 1 of 13	ENSP00000496593.1	B1AK53-1
	ESPN	ENST00000636330.1	TSL:5	c.103C>T	p.Leu35Leu	synonymous	Exon 1 of 11	ENSP00000490186.1	A0A1B0GUN9

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152000 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000758 AC: 10 AN: 1319616 Hom.: 0 Cov.: 31 AF XY: 0.00000615 AC XY: 4 AN XY: 650634

African (AFR) AF: 0.000227 AC: 6 AN: 26410

American (AMR) AF: 0.00 AC: 0 AN: 26078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22984

East Asian (EAS) AF: 0.00 AC: 0 AN: 29280

South Asian (SAS) AF: 0.00 AC: 0 AN: 72608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3890

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1050878

Other (OTH) AF: 0.0000733 AC: 4 AN: 54590

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152108 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74382

African (AFR) AF: 0.000217 AC: 9 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		0.90
PromoterAI		0.026	Neutral
Mutation Taster		=100/0	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: rs1024918977; hg19: chr1-6485118;