Genetic Variant REC114:p.Leu66Leu (chr15-73473870-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_001042367.2(REC114):c.198C>T(p.Leu66Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,587,870 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0025 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 16 hom. )

Consequence

REC114
NM_001042367.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.261

Variant links:

Genes affected

REC114 (HGNC:25065): (REC114 meiotic recombination protein) The protein encoded by this gene is orthologous to the mouse meiotic recombination protein REC114, which is involved in DNA double-strand break formation during meiosis. The encoded protein is conserved in most eukaryotes and was first discovered and characterized in yeast. [provided by RefSeq, Feb 2017]

REC114 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 15-73473870-C-T is Benign according to our data. Variant chr15-73473870-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2645531.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.261 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00226 (3242/1435550) while in subpopulation MID AF= 0.035 (200/5718). AF 95% confidence interval is 0.031. There are 16 homozygotes in gnomad4_exome. There are 1692 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REC114	NM_001042367.2 link	c.198C>T	p.Leu66Leu	synonymous_variant	Exon 2 of 6	ENST00000331090.11	NP_001035826.1
REC114	NM_001348772.2 link	c.198C>T	p.Leu66Leu	synonymous_variant	Exon 2 of 5		NP_001335701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REC114	ENST00000331090.11 link	c.198C>T	p.Leu66Leu	synonymous_variant	Exon 2 of 6	1	NM_001042367.2	ENSP00000328423.6		Q7Z4M0
REC114	ENST00000560581.1 link	c.198C>T	p.Leu66Leu	synonymous_variant	Exon 2 of 5	2		ENSP00000452908.1		H0YKR2

Frequencies

GnomAD3 genomes

AF:

0.00249

AC:

379

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00668

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00259

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00302

AC:

654

AN:

216226

Hom.:

AF XY:

0.00309

AC XY:

359

AN XY:

116072

show subpopulations

Gnomad AFR exome

AF:

0.000507

Gnomad AMR exome

AF:

0.00384

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.0000607

Gnomad SAS exome

AF:

0.00289

Gnomad FIN exome

AF:

0.00113

Gnomad NFE exome

AF:

0.00272

Gnomad OTH exome

AF:

0.00735

GnomAD4 exome

AF:

0.00226

AC:

3242

AN:

1435550

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

1692

AN XY:

711800

show subpopulations

Gnomad4 AFR exome

AF:

0.00117

Gnomad4 AMR exome

AF:

0.00378

Gnomad4 ASJ exome

AF:

0.0145

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.00347

Gnomad4 FIN exome

AF:

0.000586

Gnomad4 NFE exome

AF:

0.00173

Gnomad4 OTH exome

AF:

0.00429

GnomAD4 genome

AF:

0.00249

AC:

380

AN:

152320

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

201

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00667

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00259

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00313

Hom.:

Bravo

AF:

0.00297

Asia WGS

AF:

0.00116

AC:

AN:

3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

REC114: BP4, BS2 -

REC114-related disorder

Benign:1

Apr 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

7.9

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over