ENST00000323977.7:c.-208G>A

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRE11	NM_005591.4	c.-106+5G>A		splice_region_variant, intron_variant	Intron 1 of 19	ENST00000323929.8	NP_005582.1
ANKRD49	NM_017704.3	c.-340C>T		upstream_gene_variant		ENST00000544612.6	NP_060174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.-106+5G>A		splice_region_variant, intron_variant	Intron 1 of 19	1	NM_005591.4	ENSP00000325863.4
ANKRD49	ENST00000544612.6	c.-340C>T		upstream_gene_variant		1	NM_017704.3	ENSP00000440396.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0500

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.0166

Gnomad4 AMR AF: 0.0469

Gnomad4 ASJ AF: 0.0392

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0190

Gnomad4 FIN AF: 0.0696

Gnomad4 NFE AF: 0.0911

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0587 Hom.: 143

Bravo AF: 0.0538

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia-like disorder 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.0
DANN	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs1805363; hg19: chr11-94226952;