1-6451926-A-G

Variant names:

• chr1-6451926-A-G
• NM_031475.3:c.2155A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_031475.3(ESPN):​c.2155A>G​(p.Ser719Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S719R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-6451926-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 4420.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3418461).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESPN	NM_031475.3	c.2155A>G	p.Ser719Gly	missense_variant	Exon 10 of 13	ENST00000645284.1	NP_113663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESPN	ENST00000645284.1	c.2155A>G	p.Ser719Gly	missense_variant	Exon 10 of 13		NM_031475.3	ENSP00000496593.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458666 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725382

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;T;T;.;.;T;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.83	.;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.8	L;.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.8	.;.;N;N;.;.;.;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.0020	.;.;D;T;.;.;.;.;.
Sift4G	Benign	0.16	.;.;T;T;T;.;T;.;.
Polyphen		0.27	B;.;B;.;B;.;.;.;.
Vest4		0.22, 0.24, 0.25
MutPred		0.22		Loss of glycosylation at S719 (P = 0.0017);Loss of glycosylation at S719 (P = 0.0017);Loss of glycosylation at S719 (P = 0.0017);.;.;.;.;.;.;
MVP		0.78
MPC		0.27
ClinPred		0.75	D
GERP RS		4.0
Varity_R		0.20
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6511986;