11-94490879-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005591.4(MRE11):c.107C>A(p.Thr36Lys) 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. T36A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.15

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4	c.107C>A	p.Thr36Lys	missense_variant	3/20	ENST00000323929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRE11	ENST00000323929.8	c.107C>A	p.Thr36Lys	missense_variant	3/20	1	NM_005591.4	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;.;.;D;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.7	L;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.2	N;N;N;N;N;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		0.99	D;.;D;.;.;.;.
Vest4		0.78
MutPred		0.78		.;Gain of ubiquitination at T39 (P = 0.0351);.;.;.;.;.;
MVP		0.84
MPC		0.39
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.94
gMVP		0.85

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: rs768676557; hg19: chr11-94224045;