chr14-99894754-T-C

Position:

• chr14-99894754-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_004434.3(EML1):​c.673T>C​(p.Trp225Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EML1 NM_004434.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

Genes affected

EML1 (HGNC:3330): (EMAP like 1) Human echinoderm microtubule-associated protein-like is a strong candidate for the Usher syndrome type 1A gene. Usher syndromes (USHs) are a group of genetic disorders consisting of congenital deafness, retinitis pigmentosa, and vestibular dysfunction of variable onset and severity depending on the genetic type. The disease process in USHs involves the entire brain and is not limited to the posterior fossa or auditory and visual systems. The USHs are catagorized as type I (USH1A, USH1B, USH1C, USH1D, USH1E and USH1F), type II (USH2A and USH2B) and type III (USH3). The type I is the most severe form. Gene loci responsible for these three types are all mapped. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EML1. . Gene score misZ 2.4519 (greater than the threshold 3.09). Trascript score misZ 3.3424 (greater than threshold 3.09). GenCC has associacion of gene with band heterotopia of brain, subcortical band heterotopia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 14-99894754-T-C is Pathogenic according to our data. Variant chr14-99894754-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 254260.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EML1	NM_004434.3	c.673T>C	p.Trp225Arg	missense_variant	6/22	ENST00000262233.11	NP_004425.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EML1	ENST00000262233.11	c.673T>C	p.Trp225Arg	missense_variant	6/22	1	NM_004434.3	ENSP00000262233	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Band heterotopia of brain Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 19, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T;T;.;T;.;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Uncertain	2.7	.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-13	D;D;.;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;.;D;D;D
Sift4G	Uncertain	0.0020	D;D;.;D;D;D
Polyphen		0.027, 0.18, 0.12	.;B;.;B;B;.
Vest4		0.88, 0.90, 0.88
MutPred		0.77		.;.;.;Gain of catalytic residue at Y227 (P = 0.0062);.;.;
MVP		0.59
MPC		1.0
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs886037937; hg19: chr14-100361091;