rs539025487

chr1-225937707-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003240.5(LEFTY2):c.835A>G(p.Lys279Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000483 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: LEFTY2 NM_003240.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022280872).
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEFTY2	NM_003240.5	c.835A>G	p.Lys279Glu	missense_variant	4/4	ENST00000366820.10
LEFTY2	NM_001172425.3	c.733A>G	p.Lys245Glu	missense_variant	5/5
LEFTY2	XM_011544266.2	c.*208A>G		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEFTY2	ENST00000366820.10	c.835A>G	p.Lys279Glu	missense_variant	4/4	1	NM_003240.5	P1
LEFTY2	ENST00000420304.6	c.733A>G	p.Lys245Glu	missense_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000558 AC: 14 AN: 250710 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135548

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461040 Hom.: 0 Cov.: 29 AF XY: 0.0000385 AC XY: 28 AN XY: 726638

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74482

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000185

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Left-right axis malformations Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 05, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 536417). This variant has not been reported in the literature in individuals affected with LEFTY2-related conditions. This variant is present in population databases (rs539025487, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 279 of the LEFTY2 protein (p.Lys279Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	0.77
Dann	Benign	0.61
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.060	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.6	N;N
REVEL	Benign	0.21
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.062
MVP		0.62
MPC		0.26
ClinPred		0.0022	T
GERP RS		4.2
Varity_R		0.084
gMVP		0.63

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: rs539025487; hg19: chr1-226125407;