11-94437206-G-C

Variant names:

• chr11-94437206-G-C
• rs137852759
• NM_005591.4:c.1897C>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.1897C>G​(p.Arg633Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35

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=0.087738305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRE11	NM_005591.4	c.1897C>G	p.Arg633Gly	missense_variant	Exon 17 of 20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.1897C>G	p.Arg633Gly	missense_variant	Exon 17 of 20	1	NM_005591.4	ENSP00000325863.4
MRE11	ENST00000323977.7	c.1813C>G	p.Arg605Gly	missense_variant	Exon 16 of 19	1		ENSP00000326094.3
MRE11	ENST00000407439.7	c.1906C>G	p.Arg636Gly	missense_variant	Exon 17 of 20	2		ENSP00000385614.3
MRE11	ENST00000393241.8	c.1894C>G	p.Arg632Gly	missense_variant	Exon 17 of 20	5		ENSP00000376933.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251072 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460604 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.088	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	L;.;.;.
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.099
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.026	D;D;T;D
Polyphen		0.0010	B;.;B;.
Vest4		0.14
MutPred		0.22		.;Loss of MoRF binding (P = 0.0174);.;.;
MVP		0.67
MPC		0.11
ClinPred		0.49	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.45

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: rs137852759; hg19: chr11-94170372;