15-73473870-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001042367.2(REC114):c.198C>T(p.Leu66=) 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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.261

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]

ACMG classification

Verdict is Benign. Variant got -19 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_multiple_submitters_no_conflicts, 2 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 GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REC114	NM_001042367.2	c.198C>T	p.Leu66=	synonymous_variant	2/6	ENST00000331090.11
REC114	NM_001348772.2	c.198C>T	p.Leu66=	synonymous_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REC114	ENST00000331090.11	c.198C>T	p.Leu66=	synonymous_variant	2/6	1	NM_001042367.2	P1
REC114	ENST00000560581.1	c.198C>T	p.Leu66=	synonymous_variant	2/5	2

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 379 AN: 152202 Hom.: 5 Cov.: 32

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.: 3 AF XY: 0.00309 AC XY: 359 AN XY: 116072

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.: 16 Cov.: 29 AF XY: 0.00238 AC XY: 1692 AN XY: 711800

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.: 6 Cov.: 32 AF XY: 0.00270 AC XY: 201 AN XY: 74470

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.: 1

Bravo AF: 0.00297

Asia WGS AF: 0.00116 AC: 4 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

REC114: BP4, BS2 -

REC114-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2019

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

Other links and lift over

dbSNP: rs140303255; hg19: chr15-73766211; COSMIC: COSV105891882;