rs369405672

chr1-6451755-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_031475.3(ESPN):c.2061+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 1,611,518 control chromosomes in the GnomAD database, including 6 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (6 hom.)
• Consequence: ESPN NM_031475.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001354
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.368

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-6451755-G-A is Benign according to our data. Variant chr1-6451755-G-A is described in ClinVar as [Benign]. Clinvar id is 226634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000394 (60/152350) while in subpopulation SAS AF= 0.00745 (36/4832). AF 95% confidence interval is 0.00553. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPN	NM_031475.3	c.2061+7G>A		splice_region_variant, intron_variant		ENST00000645284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPN	ENST00000645284.1	c.2061+7G>A		splice_region_variant, intron_variant			NM_031475.3	P1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00128 AC: 309 AN: 241866 Hom.: 1 AF XY: 0.00155 AC XY: 205 AN XY: 132230

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00813

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.000286

Gnomad OTH exome AF: 0.000510

GnomAD4 exome AF: 0.000716 AC: 1045 AN: 1459168 Hom.: 6 Cov.: 32 AF XY: 0.000876 AC XY: 636 AN XY: 725810

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00223

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00680

Gnomad4 FIN exome AF: 0.000134

Gnomad4 NFE exome AF: 0.000295

Gnomad4 OTH exome AF: 0.000863

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74500

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00745

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.000166

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 15, 2015

c.2061+7G>A in intron 9 of ESPN: This variant is not expected to have clinical s ignificance because it has been identified in 0.9% (135/15134) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; rs369405672). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	7.1
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
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

Publications

LitVar

Other links and lift over

dbSNP: rs369405672; hg19: chr1-6511815;