NM_004434.3:c.2096-538A>G

Variant names:

• chr14-99937279-A-G
• rs11160562
• NM_004434.3:c.2096-538A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004434.3(EML1):​c.2096-538A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 152,176 control chromosomes in the GnomAD database, including 45,880 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.77 (45880 hom., cov: 32)
• Consequence: EML1 NM_004434.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.419
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004434.3. 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.2096-538A>G		intron	N/A	NP_004425.2
	EML1	NM_001008707.2		c.2153-538A>G		intron	N/A	NP_001008707.1
	EML1	NM_001440375.1		c.2114-538A>G		intron	N/A	NP_001427304.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EML1	ENST00000262233.11	TSL:1 MANE Select	c.2096-538A>G		intron	N/A	ENSP00000262233.7
	EML1	ENST00000649352.1		c.2171-538A>G		intron	N/A	ENSP00000498100.1
	EML1	ENST00000334192.8	TSL:5	c.2153-538A>G		intron	N/A	ENSP00000334314.4

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117461 AN: 152058 Hom.: 45840 Cov.: 32

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.665

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.724

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.807

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.763

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.772 AC: 117549 AN: 152176 Hom.: 45880 Cov.: 32 AF XY: 0.772 AC XY: 57400 AN XY: 74392

African (AFR) AF: 0.891 AC: 37007 AN: 41532

American (AMR) AF: 0.707 AC: 10819 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 2514 AN: 3470

East Asian (EAS) AF: 0.664 AC: 3413 AN: 5138

South Asian (SAS) AF: 0.637 AC: 3073 AN: 4822

European-Finnish (FIN) AF: 0.807 AC: 8553 AN: 10604

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.732 AC: 49741 AN: 67994

Other (OTH) AF: 0.761 AC: 1608 AN: 2114

Alfa AF: 0.743 Hom.: 115977

Bravo AF: 0.769

Asia WGS AF: 0.693 AC: 2412 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.1
DANN	Benign	0.37
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11160562; hg19: chr14-100403616; COSMIC: COSV51742908;