1-6452001-G-C

Position:

• chr1-6452001-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_031475.3(ESPN):​c.2230G>C​(p.Asp744His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,094 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D744N) has been classified as Uncertain significance.

• 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: 9.71

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-6452001-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESPN	NM_031475.3	c.2230G>C	p.Asp744His	missense_variant	10/13	ENST00000645284.1	NP_113663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESPN	ENST00000645284.1	c.2230G>C	p.Asp744His	missense_variant	10/13		NM_031475.3	ENSP00000496593.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453094 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722260

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;T;D;T;.;.;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	2.0	M;.;M;.;.;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.5	.;.;D;D;.;.;.;.
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	.;.;D;D;.;.;.;.
Sift4G	Uncertain	0.0040	.;.;D;T;T;.;D;.
Polyphen		1.0	D;.;D;.;D;.;.;.
Vest4		0.67, 0.92, 0.92
MutPred		0.21		Gain of MoRF binding (P = 0.0663);Gain of MoRF binding (P = 0.0663);Gain of MoRF binding (P = 0.0663);.;.;.;.;.;
MVP		0.86
MPC		0.69
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.50

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: chr1-6512061;