11-94460981-T-G

Variant names:

• chr11-94460981-T-G
• NM_005591.4:c.1281A>C

Variant summary

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

The NM_005591.4(MRE11):​c.1281A>C​(p.Leu427Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,520 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.185

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.1281A>C	p.Leu427Phe	missense_variant	Exon 12 of 20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.1281A>C	p.Leu427Phe	missense_variant	Exon 12 of 20	1	NM_005591.4	ENSP00000325863.4
MRE11	ENST00000323977.7	c.1281A>C	p.Leu427Phe	missense_variant	Exon 12 of 19	1		ENSP00000326094.3
MRE11	ENST00000407439.7	c.1290A>C	p.Leu430Phe	missense_variant	Exon 12 of 20	2		ENSP00000385614.3
MRE11	ENST00000393241.8	c.1281A>C	p.Leu427Phe	missense_variant	Exon 12 of 20	5		ENSP00000376933.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461520 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727052

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: 0.00000180

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	0.26
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.6	M;.;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Uncertain	0.051	T;T;T;T
Polyphen		0.87	P;.;P;.
Vest4		0.46
MutPred		0.56		.;Loss of disorder (P = 0.1697);.;.;
MVP		0.72
MPC		0.34
ClinPred		0.97	D
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.21

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: chr11-94194147;