11-94467865-C-G

Position:

• chr11-94467865-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000323929.8(MRE11):​c.1046G>C​(p.Arg349Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R349Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRE11 ENST00000323929.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.70

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRE11	NM_005591.4	c.1046G>C	p.Arg349Pro	missense_variant	10/20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.1046G>C	p.Arg349Pro	missense_variant	10/20	1	NM_005591.4	ENSP00000325863	P3
MRE11	ENST00000323977.7	c.1046G>C	p.Arg349Pro	missense_variant	10/19	1		ENSP00000326094
MRE11	ENST00000407439.7	c.1055G>C	p.Arg352Pro	missense_variant	10/20	2		ENSP00000385614
MRE11	ENST00000393241.8	c.1046G>C	p.Arg349Pro	missense_variant	10/20	5		ENSP00000376933	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.8	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Uncertain	0.60
Sift	Benign	0.069	T;T;T;T
Sift4G	Benign	0.24	T;T;T;T
Polyphen		1.0	D;.;D;.
Vest4		0.74
MutPred		0.50		.;Gain of catalytic residue at R352 (P = 0.1525);.;.;
MVP		0.82
MPC		0.52
ClinPred		0.91	D
GERP RS		6.1
Varity_R		0.94
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-94201031;