14-99878513-C-G

Variant names:

• chr14-99878513-C-G
• rs886037935
• NM_004434.3:c.412C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001008707.2(EML1):​c.469C>G​(p.Arg157Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EML1 NM_001008707.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.594
• Publications: 0 publications found

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]

EML1 Gene-Disease associations (from GenCC):

• band heterotopia of brain

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• subcortical band heterotopia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12491384).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008707.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EML1	NM_004434.3	MANE Select	c.412C>G	p.Arg138Gly	missense	Exon 4 of 22	NP_004425.2
	EML1	NM_001008707.2		c.469C>G	p.Arg157Gly	missense	Exon 5 of 23	NP_001008707.1
	EML1	NM_001440375.1		c.430C>G	p.Arg144Gly	missense	Exon 4 of 22	NP_001427304.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EML1	ENST00000262233.11	TSL:1 MANE Select	c.412C>G	p.Arg138Gly	missense	Exon 4 of 22	ENSP00000262233.7
	EML1	ENST00000554479.5	TSL:1	c.373C>G	p.Arg125Gly	missense	Exon 4 of 11	ENSP00000451346.1
	EML1	ENST00000909081.1		c.586C>G	p.Arg196Gly	missense	Exon 5 of 23	ENSP00000579140.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461630 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727114

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.86
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.59
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.063
Sift	Benign	0.11	T
Sift4G	Benign	0.11	T
Polyphen		0.60	P
Vest4		0.41
MutPred		0.41		Loss of sheet (P = 0.0084)
MVP		0.068
MPC		1.5
ClinPred		0.39	T
GERP RS		1.2
Varity_R		0.097
gMVP		0.22
Mutation Taster		=88/12	polymorphism

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: rs886037935; hg19: chr14-100344850;