chr8-94664946-C-G

Position:

• chr8-94664946-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The ENST00000433389.8(ESRP1):​c.775C>G​(p.Leu259Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ESRP1 ENST00000433389.8 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.17

Genes affected

ESRP1 (HGNC:25966): (epithelial splicing regulatory protein 1) ESPR1 is an epithelial cell-type-specific splicing regulator (Warzecha et al., 2009 [PubMed 19285943]).[supplied by OMIM, Aug 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-94664946-C-G is Pathogenic according to our data. Variant chr8-94664946-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 545506.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESRP1	NM_017697.4	c.775C>G	p.Leu259Val	missense_variant	8/16	ENST00000433389.8	NP_060167.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESRP1	ENST00000433389.8	c.775C>G	p.Leu259Val	missense_variant	8/16	1	NM_017697.4	ENSP00000405738	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hearing loss, autosomal recessive 109 Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Pathogenic, for Deafness, autosomal recessive, 109. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/29107558). PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/29107558). PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/29107558). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;T;T;.;.;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.6	L;L;L;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	D;D;.;D;.;D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D;.;D;.;D;D
Sift4G	Uncertain	0.0040	D;D;.;D;.;D;D
Polyphen		1.0, 1.0	.;D;D;D;D;.;.
Vest4		0.59
MutPred		0.42		Loss of catalytic residue at L259 (P = 0.0542);Loss of catalytic residue at L259 (P = 0.0542);Loss of catalytic residue at L259 (P = 0.0542);Loss of catalytic residue at L259 (P = 0.0542);Loss of catalytic residue at L259 (P = 0.0542);Loss of catalytic residue at L259 (P = 0.0542);.;
MVP		0.45
MPC		1.5
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.78
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs1554577402; hg19: chr8-95677174; COSMIC: COSV64411974; COSMIC: COSV64411974;