chr1-6444690-T-C

Variant names:

• chr1-6444690-T-C
• rs876657461
• NM_031475.3:c.1192+8T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_031475.3(ESPN):​c.1192+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ESPN NM_031475.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001505
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.439
• 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):

• nonsyndromic genetic hearing loss

  Inheritance: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 36

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• 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)

ENSG00000231868 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-6444690-T-C is Benign according to our data. Variant chr1-6444690-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 227358.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESPN	NM_031475.3	c.1192+8T>C		splice_region_variant, intron_variant	Intron 6 of 12	ENST00000645284.1	NP_113663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESPN	ENST00000645284.1	c.1192+8T>C		splice_region_variant, intron_variant	Intron 6 of 12		NM_031475.3	ENSP00000496593.1
ESPN	ENST00000636330.1	c.1192+8T>C		splice_region_variant, intron_variant	Intron 6 of 10	5		ENSP00000490186.1
ESPN	ENST00000418286.1	c.547+8T>C		splice_region_variant, intron_variant	Intron 4 of 4	3		ENSP00000401793.1
ENSG00000231868	ENST00000419034.1	n.215+872A>G		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 04, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.1192+8T>C in intron 6 of ESPN: This variant is not expected to have clinical s ignificance because it is not located within the splice consensus sequence and i t is not predicted to impact splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.4
DANN	Benign	0.71
PhyloP100		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0
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: rs876657461; hg19: chr1-6504750;