11-94493786-C-T

Variant names:

• chr11-94493786-C-T
• rs1805363
• ENST00000323977.7:c.-208G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The ENST00000323977.7(MRE11):​c.-208G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0574 in 152,356 control chromosomes in the GnomAD database, including 370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (370 hom., cov: 32)
  • Exomes 𝑓: 0.034 (0 hom.)
• Consequence: MRE11 ENST00000323977.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.716
• Publications: 26 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]

ANKRD49 (HGNC:25970): (ankyrin repeat domain 49) Involved in positive regulation of transcription, DNA-templated. Predicted to be located in nucleus. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 11-94493786-C-T is Benign according to our data. Variant chr11-94493786-C-T is described in ClinVar as Benign. ClinVar VariationId is 306498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0892 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000323977.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	NM_005591.4	MANE Select	c.-106+5G>A		splice_region intron	N/A	NP_005582.1
	MRE11	NM_001440461.1		c.-208G>A		5_prime_UTR	Exon 1 of 21	NP_001427390.1
	MRE11	NM_001440462.1		c.-208G>A		5_prime_UTR	Exon 1 of 20	NP_001427391.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	ENST00000323977.7	TSL:1	c.-208G>A		5_prime_UTR	Exon 1 of 19	ENSP00000326094.3
	MRE11	ENST00000323929.8	TSL:1 MANE Select	c.-106+5G>A		splice_region intron	N/A	ENSP00000325863.4
	MRE11	ENST00000540013.5	TSL:1	c.-106+5G>A		splice_region intron	N/A	ENSP00000440986.1

Frequencies

GnomAD3 genomes AF: 0.0574 AC: 8739 AN: 152180 Hom.: 370 Cov.: 32

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.0696

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0911

Gnomad OTH AF: 0.0583

GnomAD4 exome AF: 0.0345 AC: 2 AN: 58 Hom.: 0 Cov.: 0 AF XY: 0.0455 AC XY: 2 AN XY: 44

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0500 AC: 2 AN: 40

Other (OTH) AF: 0.00 AC: 0 AN: 10

GnomAD4 genome AF: 0.0574 AC: 8739 AN: 152298 Hom.: 370 Cov.: 32 AF XY: 0.0561 AC XY: 4177 AN XY: 74474

African (AFR) AF: 0.0166 AC: 691 AN: 41570

American (AMR) AF: 0.0469 AC: 717 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 136 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.0190 AC: 92 AN: 4832

European-Finnish (FIN) AF: 0.0696 AC: 738 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0911 AC: 6197 AN: 68028

Other (OTH) AF: 0.0577 AC: 122 AN: 2116

Alfa AF: 0.0542 Hom.: 217

Bravo AF: 0.0538

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ataxia-telangiectasia-like disorder 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.0
DANN	Benign	0.83
PhyloP100		-0.72
PromoterAI		-0.29	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: 31
DS_DL_spliceai		0.75		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1805363; hg19: chr11-94226952;