rs13447640

Positions:

• chr11-94466555-G-A
• chr11-94466555-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005591.4(MRE11):​c.1098+1258C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 517,188 control chromosomes in the GnomAD database, including 664 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 0.046 (411 hom., cov: 32)
  • Exomes 𝑓: 0.022 (253 hom.)
• Consequence: MRE11 NM_005591.4 intron
• 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]

MIR548L (HGNC:35292): (microRNA 548l) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4	c.1098+1258C>T		intron_variant		ENST00000323929.8
MIR548L	NR_031630.1	n.26C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRE11	ENST00000323929.8	c.1098+1258C>T		intron_variant		1	NM_005591.4	P3
MIR548L	ENST00000408303.1	n.26C>T		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0464 AC: 7057 AN: 152058 Hom.: 409 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.0503

GnomAD3 exomes AF: 0.0241 AC: 5626 AN: 233402 Hom.: 192 AF XY: 0.0244 AC XY: 3117 AN XY: 127840

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.0355

Gnomad EAS exome AF: 0.000230

Gnomad SAS exome AF: 0.0448

Gnomad FIN exome AF: 0.000790

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0215 AC: 7866 AN: 365012 Hom.: 253 Cov.: 0 AF XY: 0.0234 AC XY: 4867 AN XY: 207642

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.0337

Gnomad4 EAS exome AF: 0.000158

Gnomad4 SAS exome AF: 0.0458

Gnomad4 FIN exome AF: 0.000737

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.0270

GnomAD4 genome AF: 0.0464 AC: 7060 AN: 152176 Hom.: 411 Cov.: 32 AF XY: 0.0454 AC XY: 3378 AN XY: 74402

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0365

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.0498

Alfa AF: 0.0157 Hom.: 19

Bravo AF: 0.0519

Asia WGS AF: 0.0230 AC: 79 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
DANN	Benign	0.78

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: rs13447640; hg19: chr11-94199721;