rs1060501785

chr11-94456293-C-G

Variant summary

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

The NM_005591.4(MRE11):c.1546G>C(p.Asp516His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D516V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.47

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4	c.1546G>C	p.Asp516His	missense_variant	14/20	ENST00000323929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRE11	ENST00000323929.8	c.1546G>C	p.Asp516His	missense_variant	14/20	1	NM_005591.4	P3
MRE11	ENST00000323977.7	c.1546G>C	p.Asp516His	missense_variant	14/19	1
MRE11	ENST00000407439.7	c.1555G>C	p.Asp519His	missense_variant	14/20	2
MRE11	ENST00000393241.8	c.1546G>C	p.Asp516His	missense_variant	14/20	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Apr 05, 2016

This sequence change replaces aspartic acid with histidine at codon 516 of the MRE11A protein (p.Asp516His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MRE11A-related disease. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Uncertain	2.3	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.98	D;.;P;.
Vest4		0.55
MutPred		0.17		.;Loss of loop (P = 0.0374);.;.;
MVP		0.78
MPC		0.42
ClinPred		0.92	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.19
gMVP		0.35

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: rs1060501785; hg19: chr11-94189459;