rs74578461

chr1-225939743-G-C

Variant summary

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

The NM_003240.5(LEFTY2):c.497+13C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,597,580 control chromosomes in the GnomAD database, including 76,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8009 hom., cov: 34)
  • Exomes 𝑓: 0.31 (68855 hom.)
• Consequence: LEFTY2 NM_003240.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.70

Genes affected

LEFTY2 (HGNC:3122): (left-right determination factor 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate the mature protein, which plays a role in left-right asymmetry determination of organ systems during development. The protein may also play a role in endometrial bleeding. Mutations in this gene have been associated with left-right axis malformations, particularly in the heart and lungs. Some types of infertility have been associated with dysregulated expression of this gene in the endometrium. This gene is closely linked to both a related family member and a related pseudogene. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-225939743-G-C is Benign according to our data. Variant chr1-225939743-G-C is described in ClinVar as [Benign]. Clinvar id is 138108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225939743-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEFTY2	NM_003240.5	c.497+13C>G		intron_variant		ENST00000366820.10
LEFTY2	NM_001172425.3	c.395+13C>G		intron_variant
LEFTY2	XM_011544266.2	c.497+13C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEFTY2	ENST00000366820.10	c.497+13C>G		intron_variant		1	NM_003240.5	P1
LEFTY2	ENST00000420304.6	c.395+13C>G		intron_variant		2
LEFTY2	ENST00000474493.1	n.346+13C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49063 AN: 151748 Hom.: 8009 Cov.: 34

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.337

GnomAD3 exomes AF: 0.311 AC: 65247 AN: 210088 Hom.: 10490 AF XY: 0.304 AC XY: 35547 AN XY: 116854

Gnomad AFR exome AF: 0.362

Gnomad AMR exome AF: 0.420

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.143

Gnomad SAS exome AF: 0.236

Gnomad FIN exome AF: 0.326

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.307 AC: 443228 AN: 1445714 Hom.: 68855 Cov.: 65 AF XY: 0.303 AC XY: 218021 AN XY: 718570

Gnomad4 AFR exome AF: 0.353

Gnomad4 AMR exome AF: 0.412

Gnomad4 ASJ exome AF: 0.321

Gnomad4 EAS exome AF: 0.156

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.317

Gnomad4 NFE exome AF: 0.311

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.323 AC: 49094 AN: 151866 Hom.: 8009 Cov.: 34 AF XY: 0.322 AC XY: 23932 AN XY: 74246

Gnomad4 AFR AF: 0.357

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.337

Gnomad4 NFE AF: 0.309

Gnomad4 OTH AF: 0.335

Alfa AF: 0.320 Hom.: 1411

Bravo AF: 0.331

Asia WGS AF: 0.193 AC: 671 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Left-right axis malformations Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.066
Dann	Benign	0.67

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: rs74578461; hg19: chr1-226127443; COSMIC: COSV64746410; COSMIC: COSV64746410;