1-225937602-G-C

Variant names:

• chr1-225937602-G-C
• NM_003240.5:c.940C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003240.5(LEFTY2):​c.940C>G​(p.Arg314Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R314Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LEFTY2 NM_003240.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281

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]

ENSG00000248322 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEFTY2	NM_003240.5	c.940C>G	p.Arg314Gly	missense_variant	Exon 4 of 4	ENST00000366820.10	NP_003231.2
LEFTY2	NM_001172425.3	c.838C>G	p.Arg280Gly	missense_variant	Exon 5 of 5		NP_001165896.1
LEFTY2	XM_011544266.2	c.*313C>G		3_prime_UTR_variant	Exon 4 of 4		XP_011542568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEFTY2	ENST00000366820.10	c.940C>G	p.Arg314Gly	missense_variant	Exon 4 of 4	1	NM_003240.5	ENSP00000355785.5
LEFTY2	ENST00000420304.6	c.838C>G	p.Arg280Gly	missense_variant	Exon 5 of 5	2		ENSP00000388009.2
ENSG00000248322	ENST00000513672.1	n.-45C>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461786 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;D
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.7	.;M
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.041	D;D
Polyphen		1.0	.;D
Vest4		0.24
MutPred		0.64		.;Gain of sheet (P = 0.0125);
MVP		0.72
MPC		0.79
ClinPred		1.0	D
GERP RS		-0.78
Varity_R		0.86
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-226125302;