chr11-94434611-G-A

Variant names:

• chr11-94434611-G-A
• rs601341
• NM_005591.4:c.1994+1221C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005591.4(MRE11):​c.1994+1221C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 151,674 control chromosomes in the GnomAD database, including 12,325 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (12325 hom., cov: 31)
• Consequence: MRE11 NM_005591.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.124
• Publications: 10 publications found

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]

MRE11 Gene-Disease associations (from GenCC):

• ataxia-telangiectasia-like disorder 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• prostate cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005591.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	NM_005591.4	MANE Select	c.1994+1221C>T		intron	N/A	NP_005582.1	P49959-1
	MRE11	NM_001440460.1		c.1994+1221C>T		intron	N/A	NP_001427389.1
	MRE11	NM_001440461.1		c.1994+1221C>T		intron	N/A	NP_001427390.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	ENST00000323929.8	TSL:1 MANE Select	c.1994+1221C>T		intron	N/A	ENSP00000325863.4	P49959-1
	MRE11	ENST00000323977.7	TSL:1	c.1910+1221C>T		intron	N/A	ENSP00000326094.3	P49959-2
	MRE11	ENST00000936196.1		c.1994+1221C>T		intron	N/A	ENSP00000606255.1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60410 AN: 151556 Hom.: 12313 Cov.: 31

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.421

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.399 AC: 60459 AN: 151674 Hom.: 12325 Cov.: 31 AF XY: 0.401 AC XY: 29714 AN XY: 74076

African (AFR) AF: 0.464 AC: 19196 AN: 41352

American (AMR) AF: 0.397 AC: 6038 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1285 AN: 3470

East Asian (EAS) AF: 0.419 AC: 2146 AN: 5126

South Asian (SAS) AF: 0.474 AC: 2270 AN: 4794

European-Finnish (FIN) AF: 0.360 AC: 3773 AN: 10484

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24646 AN: 67916

Other (OTH) AF: 0.417 AC: 878 AN: 2106

Alfa AF: 0.379 Hom.: 1895

Bravo AF: 0.402

Asia WGS AF: 0.445 AC: 1548 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.9
DANN	Benign	0.57
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs601341; hg19: chr11-94167777;