rs142638391

chr1-6444594-T-G

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.1104T>G(p.Phe368Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 1,614,218 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (4 hom.)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.206

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=0.008469462).
• BP6: Variant 1-6444594-T-G is Benign according to our data. Variant chr1-6444594-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 163413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6444594-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00381 (581/152332) while in subpopulation AFR AF= 0.0134 (557/41580). AF 95% confidence interval is 0.0125. There are 3 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPN	NM_031475.3	c.1104T>G	p.Phe368Leu	missense_variant	6/13	ENST00000645284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPN	ENST00000645284.1	c.1104T>G	p.Phe368Leu	missense_variant	6/13		NM_031475.3	P1
	ENST00000419034.1	n.215+968A>C		intron_variant, non_coding_transcript_variant		5
ESPN	ENST00000636330.1	c.1104T>G	p.Phe368Leu	missense_variant	6/11	5
ESPN	ENST00000418286.1	c.459T>G	p.Phe153Leu	missense_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 579 AN: 152214 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.000103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000946 AC: 238 AN: 251474 Hom.: 3 AF XY: 0.000596 AC XY: 81 AN XY: 135914

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000781

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: 0.0000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000319 AC: 467 AN: 1461886 Hom.: 4 Cov.: 32 AF XY: 0.000259 AC XY: 188 AN XY: 727244

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.000939

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: 0.00000989

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.00381 AC: 581 AN: 152332 Hom.: 3 Cov.: 33 AF XY: 0.00358 AC XY: 267 AN XY: 74488

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00409

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Phe368Leu in Exon 06 of ESPN: This variant is not expected to have clinical sign ificance because it has been identified in 1.0% (36/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs142638391). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.74	D
MetaRNN	Benign	0.0085	T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.4	M;.;M;.
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.66	T
Polyphen		1.0	D;.;D;.
Vest4		0.37
MutPred		0.40		Gain of glycosylation at S372 (P = 0.1045);Gain of glycosylation at S372 (P = 0.1045);Gain of glycosylation at S372 (P = 0.1045);.;
MVP		0.79
MPC		0.17
ClinPred		0.054	T
GERP RS		-1.3
Varity_R		0.22
gMVP		0.55

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: rs142638391; hg19: chr1-6504654;