chr14-99812518-A-C

Variant names:

• chr14-99812518-A-C
• rs12891247
• NM_004434.3:c.67+18975A>C

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+18975A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 151,456 control chromosomes in the GnomAD database, including 12,276 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 0.38 (12276 hom., cov: 31)
• Consequence: EML1 NM_004434.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0430
• Publications: 3 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EML1	NM_004434.3	c.67+18975A>C		intron_variant	Intron 1 of 21	ENST00000262233.11	NP_004425.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EML1	ENST00000262233.11	c.67+18975A>C		intron_variant	Intron 1 of 21	1	NM_004434.3	ENSP00000262233.7

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58004 AN: 151340 Hom.: 12262 Cov.: 31

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.464

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.404

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

GnomAD4 genome AF: 0.383 AC: 58058 AN: 151456 Hom.: 12276 Cov.: 31 AF XY: 0.388 AC XY: 28681 AN XY: 73920

African (AFR) AF: 0.224 AC: 9266 AN: 41422

American (AMR) AF: 0.460 AC: 7007 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1440 AN: 3464

East Asian (EAS) AF: 0.427 AC: 2196 AN: 5148

South Asian (SAS) AF: 0.551 AC: 2631 AN: 4772

European-Finnish (FIN) AF: 0.414 AC: 4298 AN: 10378

Middle Eastern (MID) AF: 0.465 AC: 133 AN: 286

European-Non Finnish (NFE) AF: 0.441 AC: 29876 AN: 67750

Other (OTH) AF: 0.407 AC: 854 AN: 2098

Alfa AF: 0.334 Hom.: 1428

Bravo AF: 0.382

Asia WGS AF: 0.449 AC: 1565 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.2
DANN	Benign	0.71
PhyloP100		0.043
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: rs12891247; hg19: chr14-100278855;