17-50375223-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_152463.4(EME1):c.15G>T(p.Lys5Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,614,050 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.014 ( 43 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 35 hom. )

Consequence

EME1
NM_152463.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.720

Variant links:

Genes affected

EME1 (HGNC:24965): (essential meiotic structure-specific endonuclease 1) This gene encodes a protein that complexes with methyl methanesulfonate-sensitive UV-sensitive 81 protein to form an endonuclease complex. The encoded protein interacts with specifc DNA structures including nicked Holliday junctions, 3'-flap structures and aberrant replication fork structures. This protein may be involved in repairing DNA damage and in maintaining genomic stability. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Oct 2009]

EME1 links:

LRRC59 (HGNC:28817): (leucine rich repeat containing 59) Enables RNA binding activity and cadherin binding activity. Predicted to be involved in positive regulation of Ras protein signal transduction and signal transduction. Located in endoplasmic reticulum and mitochondrial nucleoid. [provided by Alliance of Genome Resources, Apr 2022]

LRRC59 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022019446).

BP6

Variant 17-50375223-G-T is Benign according to our data. Variant chr17-50375223-G-T is described in ClinVar as [Benign]. Clinvar id is 710466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0137 (2088/152292) while in subpopulation AFR AF= 0.0473 (1964/41540). AF 95% confidence interval is 0.0455. There are 43 homozygotes in gnomad4. There are 1018 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EME1	NM_152463.4 link	c.15G>T	p.Lys5Asn	missense_variant	Exon 2 of 9	ENST00000338165.9	NP_689676.2	Q96AY2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EME1	ENST00000338165.9 link	c.15G>T	p.Lys5Asn	missense_variant	Exon 2 of 9	2	NM_152463.4	ENSP00000339897.4		Q96AY2-1

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2089

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0474

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00622

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.00361

AC:

907

AN:

251134

Hom.:

AF XY:

0.00262

AC XY:

356

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.0488

Gnomad AMR exome

AF:

0.00261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00140

AC:

2045

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

866

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0469

Gnomad4 AMR exome

AF:

0.00306

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000701

Gnomad4 OTH exome

AF:

0.00396

GnomAD4 genome

AF:

0.0137

AC:

2088

AN:

152292

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1018

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0473

Gnomad4 AMR

AF:

0.00621

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00254

Hom.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0470

AC:

207

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00451

AC:

548

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0040

.;T;T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.71

T;T;T;.

MetaRNN

Benign

0.0022

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;M;.;M

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.089

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Uncertain

0.020

D;D;D;D

Polyphen

0.99

D;D;.;D

Vest4

0.19

MutPred

0.053

Loss of ubiquitination at K5 (P = 0.0063);Loss of ubiquitination at K5 (P = 0.0063);Loss of ubiquitination at K5 (P = 0.0063);Loss of ubiquitination at K5 (P = 0.0063);

MVP

0.53

MPC

0.063

ClinPred

0.014

GERP RS

1.6

Varity_R

0.095

gMVP

0.069

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over