rs116413227

Positions:

• chr1-6444559-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031475.3(ESPN):​c.1069C>T​(p.Pro357Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00164 in 1,614,242 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (11 hom.)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.02

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009067357).
• BP6: Variant 1-6444559-C-T is Benign according to our data. Variant chr1-6444559-C-T is described in ClinVar as [Benign]. Clinvar id is 178607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6444559-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00848 (1292/152356) while in subpopulation AFR AF= 0.0301 (1251/41580). AF 95% confidence interval is 0.0287. There are 13 homozygotes in gnomad4. There are 596 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPN	NM_031475.3	c.1069C>T	p.Pro357Ser	missense_variant	6/13	ENST00000645284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPN	ENST00000645284.1	c.1069C>T	p.Pro357Ser	missense_variant	6/13		NM_031475.3	P1
	ENST00000419034.1	n.215+1003G>A		intron_variant, non_coding_transcript_variant		5
ESPN	ENST00000636330.1	c.1069C>T	p.Pro357Ser	missense_variant	6/11	5
ESPN	ENST00000418286.1	c.424C>T	p.Pro142Ser	missense_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.00847 AC: 1290 AN: 152238 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.0000735

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00221 AC: 555 AN: 251456 Hom.: 7 AF XY: 0.00157 AC XY: 214 AN XY: 135904

Gnomad AFR exome AF: 0.0301

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000930 AC: 1360 AN: 1461886 Hom.: 11 Cov.: 32 AF XY: 0.000773 AC XY: 562 AN XY: 727246

Gnomad4 AFR exome AF: 0.0328

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00848 AC: 1292 AN: 152356 Hom.: 13 Cov.: 33 AF XY: 0.00800 AC XY: 596 AN XY: 74500

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00191 Hom.: 6

Bravo AF: 0.0102

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00254 AC: 309

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Pro357Ser in Exon 06 of ESPN: This variant is not expected to have clinical sign ificance because it has been identified in 2.5% (93/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs116413227). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T;T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	.;D;D;D
MetaRNN	Benign	0.0091	T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.4	M;.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.0	.;.;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0040	.;.;D;D
Sift4G	Uncertain	0.027	.;.;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.64
MVP		0.88
MPC		0.64
ClinPred		0.028	T
GERP RS		3.8
Varity_R		0.35
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116413227; hg19: chr1-6504619;