14-99851039-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004434.3(EML1):c.250+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,604,730 control chromosomes in the GnomAD database, including 66,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4644 hom., cov: 31)
  • Exomes 𝑓: 0.28 (61573 hom.)
• Consequence: EML1 NM_004434.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0003956
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.70

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-99851039-G-A is Benign according to our data. Variant chr14-99851039-G-A is described in ClinVar as [Benign]. Clinvar id is 1286842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-99851039-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EML1	NM_004434.3	c.250+4G>A		splice_donor_region_variant, intron_variant		ENST00000262233.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EML1	ENST00000262233.11	c.250+4G>A		splice_donor_region_variant, intron_variant		1	NM_004434.3	P1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34228 AN: 152000 Hom.: 4640 Cov.: 31

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.226

GnomAD3 exomes AF: 0.245 AC: 61058 AN: 249392 Hom.: 8453 AF XY: 0.247 AC XY: 33325 AN XY: 134714

Gnomad AFR exome AF: 0.0918

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.149

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.264

GnomAD4 exome AF: 0.284 AC: 412355 AN: 1452612 Hom.: 61573 Cov.: 33 AF XY: 0.281 AC XY: 202190 AN XY: 720762

Gnomad4 AFR exome AF: 0.0863

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.287

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.307

Gnomad4 OTH exome AF: 0.262

GnomAD4 genome AF: 0.225 AC: 34233 AN: 152118 Hom.: 4644 Cov.: 31 AF XY: 0.224 AC XY: 16665 AN XY: 74348

Gnomad4 AFR AF: 0.0944

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.300

Gnomad4 OTH AF: 0.230

Alfa AF: 0.256 Hom.: 1675

Bravo AF: 0.208

Asia WGS AF: 0.177 AC: 615 AN: 3478

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	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	13
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00040
dbscSNV1_RF	Benign	0.046
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: rs72708401; hg19: chr14-100317376; COSMIC: COSV51748267;