rs886037936

Variant names:

• chr14-99897194-A-G
• rs886037936
• NM_004434.3:c.727A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-99897194-A-G
• chr14-99897194-A-T

Variant summary

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

The NM_004434.3(EML1):​c.727A>G​(p.Thr243Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EML1 NM_004434.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.19

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-99897194-A-G is Pathogenic according to our data. Variant chr14-99897194-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 254259.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EML1	NM_004434.3	c.727A>G	p.Thr243Ala	missense_variant	Exon 7 of 22	ENST00000262233.11	NP_004425.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EML1	ENST00000262233.11	c.727A>G	p.Thr243Ala	missense_variant	Exon 7 of 22	1	NM_004434.3	ENSP00000262233.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 30, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31710781, 31390572, 35289477, 24859200, 35102268, 35585091) -

Band heterotopia of brain Pathogenic:1

Sep 19, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	0.0025	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;T;.;T;.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.4	D;D;.;D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D;D;.;D;D;D
Sift4G	Uncertain	0.0080	D;D;.;D;D;D
Polyphen		1.0, 0.59, 1.0	.;D;.;P;D;.
Vest4		0.92, 0.81, 0.90
MutPred		0.60		.;.;.;Gain of catalytic residue at G244 (P = 0.0018);.;.;
MVP		0.28
MPC		0.77
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886037936; hg19: chr14-100363531;