1-6444559-C-T
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
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
NM_031475.3 missense
Scores
2
11
5
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: 1290AN: 152238Hom.: 13 Cov.: 33
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GnomAD3 exomes AF: 0.00221 AC: 555AN: 251456Hom.: 7 AF XY: 0.00157 AC XY: 214AN XY: 135904
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GnomAD4 exome AF: 0.000930 AC: 1360AN: 1461886Hom.: 11 Cov.: 32 AF XY: 0.000773 AC XY: 562AN XY: 727246
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GnomAD4 genome AF: 0.00848 AC: 1292AN: 152356Hom.: 13 Cov.: 33 AF XY: 0.00800 AC XY: 596AN XY: 74500
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ClinVar
Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;.;D;D
REVEL
Uncertain
Sift
Uncertain
.;.;D;D
Sift4G
Uncertain
.;.;D;D
Polyphen
D;.;D;.
Vest4
0.64
MVP
0.88
MPC
0.64
ClinPred
T
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at