14-99809361-C-G

Variant names:

• chr14-99809361-C-G
• rs4905898
• NM_004434.3:c.67+15818C>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.67+15818C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 161,526 control chromosomes in the GnomAD database, including 16,179 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 0.45 (15148 hom., cov: 32)
  • Exomes 𝑓: 0.45 (1031 hom.)
• Consequence: EML1 NM_004434.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.72
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.557 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EML1	NM_004434.3	MANE Select	c.67+15818C>G		intron	N/A	NP_004425.2
	EML1	NM_001008707.2		c.67+15818C>G		intron	N/A	NP_001008707.1
	EML1	NM_001375411.1		c.29-41492C>G		intron	N/A	NP_001362340.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EML1	ENST00000262233.11	TSL:1 MANE Select	c.67+15818C>G		intron	N/A	ENSP00000262233.7
	EML1	ENST00000554479.5	TSL:1	c.29-41492C>G		intron	N/A	ENSP00000451346.1
	EML1	ENST00000909081.1		c.67+15818C>G		intron	N/A	ENSP00000579140.1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67829 AN: 151926 Hom.: 15135 Cov.: 32

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.573

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.446

GnomAD4 exome AF: 0.451 AC: 4279 AN: 9482 Hom.: 1031 AF XY: 0.454 AC XY: 2247 AN XY: 4946

African (AFR) AF: 0.324 AC: 72 AN: 222

American (AMR) AF: 0.484 AC: 323 AN: 668

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 80 AN: 194

East Asian (EAS) AF: 0.380 AC: 187 AN: 492

South Asian (SAS) AF: 0.540 AC: 593 AN: 1098

European-Finnish (FIN) AF: 0.437 AC: 208 AN: 476

Middle Eastern (MID) AF: 0.600 AC: 18 AN: 30

European-Non Finnish (NFE) AF: 0.446 AC: 2587 AN: 5800

Other (OTH) AF: 0.420 AC: 211 AN: 502

GnomAD4 genome AF: 0.447 AC: 67893 AN: 152044 Hom.: 15148 Cov.: 32 AF XY: 0.452 AC XY: 33563 AN XY: 74324

African (AFR) AF: 0.392 AC: 16248 AN: 41458

American (AMR) AF: 0.481 AC: 7345 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1540 AN: 3468

East Asian (EAS) AF: 0.433 AC: 2240 AN: 5174

South Asian (SAS) AF: 0.575 AC: 2773 AN: 4826

European-Finnish (FIN) AF: 0.488 AC: 5143 AN: 10546

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.458 AC: 31151 AN: 67974

Other (OTH) AF: 0.449 AC: 947 AN: 2110

Alfa AF: 0.291 Hom.: 681

Bravo AF: 0.444

Asia WGS AF: 0.472 AC: 1645 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.046
DANN	Benign	0.41
PhyloP100		-5.7
PromoterAI		0.022	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs4905898; hg19: chr14-100275698;