chr14-99865589-G-A

Position:

• chr14-99865589-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EML1. . Gene score misZ 2.4519 (greater than the threshold 3.09). Trascript score misZ 3.3424 (greater than threshold 3.09). GenCC has associacion of gene with band heterotopia of brain, subcortical band heterotopia.
• 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 id is 708175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-99865589-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EML1	NM_004434.3	c.326G>A	p.Gly109Asp	missense_variant	3/22	ENST00000262233.11	NP_004425.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EML1	ENST00000262233.11	c.326G>A	p.Gly109Asp	missense_variant	3/22	1	NM_004434.3	ENSP00000262233	P1

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

GnomAD3 exomes AF: 0.00347 AC: 873 AN: 251412 Hom.: 13 AF XY: 0.00340 AC XY: 462 AN XY: 135878

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 SAS exome AF: 0.00814

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

Gnomad4 AFR exome AF: 0.0153

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0106

Gnomad4 SAS exome AF: 0.00728

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00205

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

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0185

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00148 Hom.: 3

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;.;.;T;.;T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0067	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	.;.;.;.;.;.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;D;N;D;.;D;N;N;D;D;D
REVEL	Benign	0.15
Sift	Benign	0.10	T;D;T;D;.;T;T;T;T;D;D
Sift4G	Benign	0.088	T;T;T;T;.;T;T;T;T;T;T
Polyphen		0.83, 0.38	.;.;P;.;.;.;B;P;.;.;.
Vest4		0.45, 0.53, 0.47
MVP		0.17
MPC		1.3
ClinPred		0.068	T
GERP RS		4.5
Varity_R		0.17
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs141631682; hg19: chr14-100331926;