15-73551046-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042367.2(REC114):c.442G>A(p.Val148Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 1,613,828 control chromosomes in the GnomAD database, including 440 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.030 (258 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (182 hom.)
• Consequence: REC114 NM_001042367.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.40

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017898381).
• BP6: Variant 15-73551046-G-A is Benign according to our data. Variant chr15-73551046-G-A is described in ClinVar as [Benign]. Clinvar id is 779894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0998 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REC114	NM_001042367.2	c.442G>A	p.Val148Met	missense_variant	4/6	ENST00000331090.11
REC114	NM_001348772.2	c.358G>A	p.Val120Met	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REC114	ENST00000331090.11	c.442G>A	p.Val148Met	missense_variant	4/6	1	NM_001042367.2	P1
REC114	ENST00000560581.1	c.358G>A	p.Val120Met	missense_variant	3/5	2

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4498 AN: 152162 Hom.: 257 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.00792 AC: 1967 AN: 248446 Hom.: 91 AF XY: 0.00598 AC XY: 806 AN XY: 134768

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00601

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000480

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00320 AC: 4682 AN: 1461548 Hom.: 182 Cov.: 31 AF XY: 0.00285 AC XY: 2073 AN XY: 727044

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.00669

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000469

Gnomad4 OTH exome AF: 0.00610

GnomAD4 genome AF: 0.0296 AC: 4511 AN: 152280 Hom.: 258 Cov.: 32 AF XY: 0.0287 AC XY: 2134 AN XY: 74462

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.00500 Hom.: 67

Bravo AF: 0.0334

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.100 AC: 397

ESP6500EA AF: 0.000603 AC: 5

ExAC AF: 0.00972 AC: 1175

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

REC114-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2019

This variant is classified as 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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.043	T;T
Eigen	Benign	0.074
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.10
Sift	Benign	0.086	T;T
Sift4G	Uncertain	0.042	D;D
Polyphen		0.96	D;.
Vest4		0.16
MVP		0.41
MPC		0.15
ClinPred		0.052	T
GERP RS		5.5
Varity_R		0.088
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12102004; hg19: chr15-73843387;