14-99865589-G-A

Variant names:

• chr14-99865589-G-A
• rs141631682
• NM_004434.3:c.326G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004434.3(EML1):​c.326G>A​(p.Gly109Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00157 in 1,614,194 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (20 hom.)
• Consequence: EML1 NM_004434.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.66
• Publications: 11 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: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• subcortical band heterotopia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066743195).
• BP6: Variant 14-99865589-G-A is Benign according to our data. Variant chr14-99865589-G-A is described in ClinVar as Benign. ClinVar VariationId is 708175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00498 (758/152326) while in subpopulation EAS AF = 0.0185 (96/5186). AF 95% confidence interval is 0.0155. There are 3 homozygotes in GnomAd4. There are 386 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.326G>A	p.Gly109Asp	missense	Exon 3 of 22	NP_004425.2	O00423-1
	EML1	NM_001008707.2		c.326G>A	p.Gly109Asp	missense	Exon 3 of 23	NP_001008707.1	O00423-3
	EML1	NM_001440375.1		c.344G>A	p.Gly115Asp	missense	Exon 3 of 22	NP_001427304.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EML1	ENST00000262233.11	TSL:1 MANE Select	c.326G>A	p.Gly109Asp	missense	Exon 3 of 22	ENSP00000262233.7	O00423-1
	EML1	ENST00000554479.5	TSL:1	c.287G>A	p.Gly96Asp	missense	Exon 3 of 11	ENSP00000451346.1	G3V3N9
	EML1	ENST00000909081.1		c.500G>A	p.Gly167Asp	missense	Exon 4 of 23	ENSP00000579140.1

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152208 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00347 AC: 873 AN: 251412 AF XY: 0.00340

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0195

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00122 AC: 1778 AN: 1461868 Hom.: 20 Cov.: 32 AF XY: 0.00131 AC XY: 955 AN XY: 727232

African (AFR) AF: 0.0153 AC: 512 AN: 33478

American (AMR) AF: 0.000649 AC: 29 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0106 AC: 422 AN: 39698

South Asian (SAS) AF: 0.00728 AC: 628 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1112008

Other (OTH) AF: 0.00205 AC: 124 AN: 60394

GnomAD4 genome AF: 0.00498 AC: 758 AN: 152326 Hom.: 3 Cov.: 32 AF XY: 0.00518 AC XY: 386 AN XY: 74502

African (AFR) AF: 0.0144 AC: 598 AN: 41576

American (AMR) AF: 0.000849 AC: 13 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0185 AC: 96 AN: 5186

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68016

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00214 Hom.: 4

Bravo AF: 0.00561

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00364 AC: 442

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.15
Sift	Benign	0.10	T
Sift4G	Benign	0.088	T
Polyphen		0.83	P
Vest4		0.45
MVP		0.17
MPC		1.3
ClinPred		0.068	T
GERP RS		4.5
PromoterAI		-0.011	Neutral
Varity_R		0.17
gMVP		0.33
Mutation Taster		=77/23	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: rs141631682; hg19: chr14-100331926;