chr17-50378832-T-C

Variant names:

• chr17-50378832-T-C
• rs12450550
• NM_152463.4:c.1049T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152463.4(EME1):​c.1049T>C​(p.Ile350Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,614,056 control chromosomes in the GnomAD database, including 55,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3777 hom., cov: 32)
  • Exomes 𝑓: 0.26 (52049 hom.)
• Consequence: EME1 NM_152463.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04
• Publications: 41 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004383743).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152463.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EME1	NM_152463.4	MANE Select	c.1049T>C	p.Ile350Thr	missense	Exon 5 of 9	NP_689676.2
	EME1	NM_001166131.2		c.1049T>C	p.Ile350Thr	missense	Exon 5 of 9	NP_001159603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EME1	ENST00000338165.9	TSL:2 MANE Select	c.1049T>C	p.Ile350Thr	missense	Exon 5 of 9	ENSP00000339897.4
	EME1	ENST00000511648.6	TSL:1	c.1049T>C	p.Ile350Thr	missense	Exon 4 of 8	ENSP00000421700.2
	EME1	ENST00000510007.5	TSL:1	n.621T>C		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30902 AN: 152060 Hom.: 3776 Cov.: 32

Gnomad AFR AF: 0.0835

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0862

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.227 AC: 57084 AN: 251464 AF XY: 0.223

Gnomad AFR exome AF: 0.0804

Gnomad AMR exome AF: 0.290

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.0731

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.272

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.259 AC: 378471 AN: 1461878 Hom.: 52049 Cov.: 35 AF XY: 0.255 AC XY: 185253 AN XY: 727244

African (AFR) AF: 0.0756 AC: 2531 AN: 33478

American (AMR) AF: 0.285 AC: 12750 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 4066 AN: 26136

East Asian (EAS) AF: 0.0884 AC: 3510 AN: 39700

South Asian (SAS) AF: 0.131 AC: 11312 AN: 86258

European-Finnish (FIN) AF: 0.308 AC: 16469 AN: 53418

Middle Eastern (MID) AF: 0.145 AC: 835 AN: 5768

European-Non Finnish (NFE) AF: 0.282 AC: 313154 AN: 1112002

Other (OTH) AF: 0.229 AC: 13844 AN: 60396

GnomAD4 genome AF: 0.203 AC: 30905 AN: 152178 Hom.: 3777 Cov.: 32 AF XY: 0.201 AC XY: 14990 AN XY: 74402

African (AFR) AF: 0.0833 AC: 3460 AN: 41550

American (AMR) AF: 0.232 AC: 3547 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 565 AN: 3466

East Asian (EAS) AF: 0.0866 AC: 448 AN: 5176

South Asian (SAS) AF: 0.129 AC: 623 AN: 4824

European-Finnish (FIN) AF: 0.310 AC: 3284 AN: 10584

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18429 AN: 67964

Other (OTH) AF: 0.189 AC: 399 AN: 2114

Alfa AF: 0.239 Hom.: 16018

Bravo AF: 0.194

TwinsUK AF: 0.297 AC: 1103

ALSPAC AF: 0.275 AC: 1061

ESP6500AA AF: 0.0810 AC: 357

ESP6500EA AF: 0.261 AC: 2244

ExAC AF: 0.224 AC: 27188

Asia WGS AF: 0.130 AC: 451 AN: 3478

EpiCase AF: 0.254

EpiControl AF: 0.253

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.17
Sift	Benign	0.060	T
Sift4G	Benign	0.086	T
Polyphen		0.80	P
Vest4		0.069
MPC		0.080
ClinPred		0.011	T
GERP RS		2.1
Varity_R		0.082
gMVP		0.44
Mutation Taster		=97/3	polymorphism (auto)

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: rs12450550; hg19: chr17-48456193; COSMIC: COSV56813840; COSMIC: COSV56813840;