1-6424820-A-G

Position:

• chr1-6424820-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031475.3(ESPN):​c.-136A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 885,898 control chromosomes in the GnomAD database, including 31,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (13073 hom., cov: 33)
  • Exomes 𝑓: 0.21 (18078 hom.)
• Consequence: ESPN NM_031475.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.61

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-6424820-A-G is Benign according to our data. Variant chr1-6424820-A-G is described in ClinVar as [Benign]. Clinvar id is 1265345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESPN	NM_031475.3	c.-136A>G		5_prime_UTR_variant	1/13	ENST00000645284.1	NP_113663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESPN	ENST00000645284	c.-136A>G		5_prime_UTR_variant	1/13		NM_031475.3	ENSP00000496593.1
ESPN	ENST00000636330	c.-136A>G		5_prime_UTR_variant	1/11	5		ENSP00000490186.1

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51758 AN: 151172 Hom.: 13030 Cov.: 33

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.312

GnomAD4 exome AF: 0.205 AC: 150703 AN: 734618 Hom.: 18078 Cov.: 10 AF XY: 0.205 AC XY: 72994 AN XY: 356690

Gnomad4 AFR exome AF: 0.747

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.181

Gnomad4 SAS exome AF: 0.222

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.233

GnomAD4 genome AF: 0.343 AC: 51860 AN: 151280 Hom.: 13073 Cov.: 33 AF XY: 0.337 AC XY: 24926 AN XY: 73914

Gnomad4 AFR AF: 0.718

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.314

Alfa AF: 0.115 Hom.: 187

Bravo AF: 0.363

Asia WGS AF: 0.237 AC: 789 AN: 3326

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.4
DANN	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs188079860; hg19: chr1-6484880;