14-99850906-C-G

Position:

• chr14-99850906-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004434.3(EML1):​c.121C>G​(p.Leu41Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EML1 NM_004434.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EML1	NM_004434.3	c.121C>G	p.Leu41Val	missense_variant	2/22	ENST00000262233.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EML1	ENST00000262233.11	c.121C>G	p.Leu41Val	missense_variant	2/22	1	NM_004434.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.121C>G (p.L41V) alteration is located in exon 2 (coding exon 2) of the EML1 gene. This alteration results from a C to G substitution at nucleotide position 121, causing the leucine (L) at amino acid position 41 to be replaced by a valine (V). 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	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;T;T;.;.;T;.;T;T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.7	.;.;.;.;.;.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.0	N;D;N;D;.;D;N;N;N;D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;D;D;.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.;D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;.;.;D;D;.;.;.
Vest4		0.70, 0.68, 0.72
MutPred		0.22		.;.;.;.;.;.;Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);.;.;.;
MVP		0.52
MPC		1.5
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.60
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-100317243;