rs201153937

Positions:

• chr11-94461003-T-C
• chr11-94461003-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005591.4(MRE11):​c.1259A>G​(p.Lys420Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K420T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.917

Genes affected

MRE11 (HGNC:7230): (MRE11 homolog, double strand break repair nuclease) This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [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
• BP4: Computational evidence support a benign effect (MetaRNN=0.12979451).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4	c.1259A>G	p.Lys420Arg	missense_variant	12/20	ENST00000323929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRE11	ENST00000323929.8	c.1259A>G	p.Lys420Arg	missense_variant	12/20	1	NM_005591.4	P3
MRE11	ENST00000323977.7	c.1259A>G	p.Lys420Arg	missense_variant	12/19	1
MRE11	ENST00000407439.7	c.1268A>G	p.Lys423Arg	missense_variant	12/20	2
MRE11	ENST00000393241.8	c.1259A>G	p.Lys420Arg	missense_variant	12/20	5		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ataxia-telangiectasia-like disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 23, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MRE11-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 420 of the MRE11 protein (p.Lys420Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T;.;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.46	N;.;N;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.44	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.36	T;T;T;T
Sift4G	Benign	0.63	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.11
MutPred		0.33		.;Loss of ubiquitination at K423 (P = 0.011);.;.;
MVP		0.52
MPC		0.070
ClinPred		0.28	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.10

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: rs201153937; hg19: chr11-94194169;