rs73517551

Variant names:

• chr11-94492783-G-A
• rs73517551
• NM_005591.4:c.19C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-94492783-G-A
• chr11-94492783-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001440471.1(MRE11):​c.-197C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000762 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: MRE11 NM_001440471.1 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.001772
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 4.42
• Publications: 4 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023215353).
• BP6: Variant 11-94492783-G-A is Benign according to our data. Variant chr11-94492783-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141030.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440471.1. 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.19C>T	p.Leu7Phe	missense splice_region	Exon 2 of 20	NP_005582.1	P49959-1
	MRE11	NM_001440471.1		c.-197C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 20	NP_001427400.1
	MRE11	NM_001440479.1		c.-197C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 19	NP_001427408.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	ENST00000323929.8	TSL:1 MANE Select	c.19C>T	p.Leu7Phe	missense splice_region	Exon 2 of 20	ENSP00000325863.4	P49959-1
	MRE11	ENST00000323977.7	TSL:1	c.19C>T	p.Leu7Phe	missense splice_region	Exon 2 of 19	ENSP00000326094.3	P49959-2
	MRE11	ENST00000540013.5	TSL:1	c.19C>T	p.Leu7Phe	missense splice_region	Exon 2 of 8	ENSP00000440986.1	F5GXT0

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000107 AC: 27 AN: 251464 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461678 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 727136

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00137 AC: 46 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111934

Other (OTH) AF: 0.0000497 AC: 3 AN: 60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000111022), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74444

African (AFR) AF: 0.00164 AC: 68 AN: 41546

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000548

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Ataxia-telangiectasia-like disorder (1)
-	1	-	Ataxia-telangiectasia-like disorder 1 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.21
Sift	Benign	0.072	T
Sift4G	Benign	0.20	T
Polyphen		0.67	P
Vest4		0.21
MVP		0.73
MPC		0.14
ClinPred		0.064	T
GERP RS		4.1
Varity_R		0.20
gMVP		0.40
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.050		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: rs73517551; hg19: chr11-94225949;