rs1554577402

Variant names:

• chr8-94664946-C-G
• rs1554577402
• NM_017697.4:c.775C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP5_Moderate

The NM_017697.4(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 (★). ClinVar reports functional evidence for this variant: "SCV000883262: "Well-established functional studies show a deleterious effect" (https://www.ncbi.nlm.nih.gov/pubmed/29107558).".

• Frequency: Genomes: not found (cov: 31)
• Consequence: ESRP1 NM_017697.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.17
• Publications: 1 publications found

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]

ESRP1 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• hearing loss, autosomal recessive 109

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000883262: "Well-established functional studies show a deleterious effect" (https://www.ncbi.nlm.nih.gov/pubmed/29107558).
• 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 VariationId is 545506.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017697.4. 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
	ESRP1	NM_017697.4	MANE Select	c.775C>G	p.Leu259Val	missense	Exon 8 of 16	NP_060167.2	Q6NXG1-1
	ESRP1	NM_001034915.3		c.775C>G	p.Leu259Val	missense	Exon 8 of 16	NP_001030087.2	Q6NXG1-3
	ESRP1	NM_001122826.2		c.775C>G	p.Leu259Val	missense	Exon 8 of 15	NP_001116298.1	Q6NXG1-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRP1	ENST00000433389.8	TSL:1 MANE Select	c.775C>G	p.Leu259Val	missense	Exon 8 of 16	ENSP00000405738.2	Q6NXG1-1
	ESRP1	ENST00000358397.9	TSL:1	c.775C>G	p.Leu259Val	missense	Exon 8 of 16	ENSP00000351168.5	Q6NXG1-3
	ESRP1	ENST00000423620.6	TSL:1	c.775C>G	p.Leu259Val	missense	Exon 8 of 15	ENSP00000407349.2	Q6NXG1-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Hearing loss, autosomal recessive 109 (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.42		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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

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