14-99850924-A-C

Position:

• chr14-99850924-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BS1_Supporting

The NM_004434.3(EML1):​c.139A>C​(p.Met47Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000499 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: EML1 NM_004434.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.11052674).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000499 (73/1461892) while in subpopulation NFE AF= 0.000062 (69/1112010). AF 95% confidence interval is 0.0000499. There are 0 homozygotes in gnomad4_exome. There are 32 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EML1	NM_004434.3	c.139A>C	p.Met47Leu	missense_variant	2/22	ENST00000262233.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EML1	ENST00000262233.11	c.139A>C	p.Met47Leu	missense_variant	2/22	1	NM_004434.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251488 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461892 Hom.: 0 Cov.: 30 AF XY: 0.0000440 AC XY: 32 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000620

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.139A>C (p.M47L) alteration is located in exon 2 (coding exon 2) of the EML1 gene. This alteration results from a A to C substitution at nucleotide position 139, causing the methionine (M) at amino acid position 47 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.76
DEOGEN2	Benign	0.011	T;T;T;T;.;.;T;.;T;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T;D;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.63	.;.;.;.;.;.;N;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.57	N;N;N;N;.;N;N;N;N;N;N
REVEL	Benign	0.073
Sift	Benign	1.0	T;T;T;T;.;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;.;T;T;T;T;T;T
Polyphen		0.0, 0.0010	.;.;B;.;.;.;B;B;.;.;.
Vest4		0.46, 0.43, 0.43
MutPred		0.23		.;.;.;.;.;.;Gain of catalytic residue at M47 (P = 0.0722);Gain of catalytic residue at M47 (P = 0.0722);.;.;.;
MVP		0.19
MPC		0.52
ClinPred		0.18	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.094

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: rs780402565; hg19: chr14-100317261;