1-6444559-C-T

Variant names:

• chr1-6444559-C-T
• rs116413227
• NM_031475.3:c.1069C>T

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: 7.02
• Publications: 3 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: Benign. The variant received -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 VariationId is 178607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	NM_031475.3	MANE Select	c.1069C>T	p.Pro357Ser	missense	Exon 6 of 13	NP_113663.2
	ESPN	NM_001367474.1		c.1069C>T	p.Pro357Ser	missense	Exon 6 of 15	NP_001354403.1
	ESPN	NM_001367473.1		c.1069C>T	p.Pro357Ser	missense	Exon 6 of 14	NP_001354402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	ENST00000645284.1	MANE Select	c.1069C>T	p.Pro357Ser	missense	Exon 6 of 13	ENSP00000496593.1
	ESPN	ENST00000636330.1	TSL:5	c.1069C>T	p.Pro357Ser	missense	Exon 6 of 11	ENSP00000490186.1
	ESPN	ENST00000418286.1	TSL:3	c.424C>T	p.Pro142Ser	missense	Exon 4 of 5	ENSP00000401793.1

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

GnomAD2 exomes AF: 0.00221 AC: 555 AN: 251456 AF XY: 0.00157

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 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

African (AFR) AF: 0.0328 AC: 1098 AN: 33480

American (AMR) AF: 0.00143 AC: 64 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000809 AC: 90 AN: 1112008

Other (OTH) AF: 0.00171 AC: 103 AN: 60396

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

African (AFR) AF: 0.0301 AC: 1251 AN: 41580

American (AMR) AF: 0.00176 AC: 27 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00301 Hom.: 7

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0091	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	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
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs116413227; hg19: chr1-6504619;