8-94643327-C-A

Position:

• chr8-94643327-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017697.4(ESRP1):​c.286C>A​(p.Leu96Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ESRP1 NM_017697.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2659918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESRP1	NM_017697.4	c.286C>A	p.Leu96Met	missense_variant	3/16	ENST00000433389.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESRP1	ENST00000433389.8	c.286C>A	p.Leu96Met	missense_variant	3/16	1	NM_017697.4	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460454 Hom.: 0 Cov.: 29 AF XY: 0.00000550 AC XY: 4 AN XY: 726642

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

The c.286C>A (p.L96M) alteration is located in exon 3 (coding exon 3) of the ESRP1 gene. This alteration results from a C to A substitution at nucleotide position 286, causing the leucine (L) at amino acid position 96 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.78	T;.;T;T;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.99	N;N;.;N;.;N
REVEL	Benign	0.11
Sift	Uncertain	0.0060	D;D;.;D;.;D
Sift4G	Uncertain	0.019	D;D;.;D;.;D
Polyphen		1.0, 0.94, 0.84	.;D;D;P;P;.
Vest4		0.43
MutPred		0.35		Gain of catalytic residue at V92 (P = 0.0208);Gain of catalytic residue at V92 (P = 0.0208);Gain of catalytic residue at V92 (P = 0.0208);Gain of catalytic residue at V92 (P = 0.0208);Gain of catalytic residue at V92 (P = 0.0208);Gain of catalytic residue at V92 (P = 0.0208);
MVP		0.22
MPC		1.4
ClinPred		0.90	D
GERP RS		4.0
Varity_R		0.23
gMVP		0.32

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: rs1817704177; hg19: chr8-95655555;