chr11-94459460-C-G

Variant names:

• chr11-94459460-C-G
• NM_005591.4:c.1448G>C

Variant summary

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

The NM_005591.4(MRE11):​c.1448G>C​(p.Arg483Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.74

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 rank	MANE	Protein	UniProt
MRE11	NM_005591.4	c.1448G>C	p.Arg483Pro	missense_variant	Exon 13 of 20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.1448G>C	p.Arg483Pro	missense_variant	Exon 13 of 20	1	NM_005591.4	ENSP00000325863.4
MRE11	ENST00000323977.7	c.1448G>C	p.Arg483Pro	missense_variant	Exon 13 of 19	1		ENSP00000326094.3
MRE11	ENST00000407439.7	c.1457G>C	p.Arg486Pro	missense_variant	Exon 13 of 20	2		ENSP00000385614.3
MRE11	ENST00000393241.8	c.1448G>C	p.Arg483Pro	missense_variant	Exon 13 of 20	5		ENSP00000376933.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461738 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.6	M;.;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Benign	0.067	T;T;T;T
Polyphen		0.78	P;.;P;.
Vest4		0.70
MutPred		0.35		.;Loss of MoRF binding (P = 0.0104);.;.;
MVP		0.79
MPC		0.33
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.69
gMVP		0.53

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: chr11-94192626;