rs747778361

chr1-225937506-T-Cchr1-225937506-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003240.5(LEFTY2):c.1036A>G(p.Met346Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. M346L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LEFTY2 NM_003240.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.97

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEFTY2	NM_003240.5	c.1036A>G	p.Met346Val	missense_variant	4/4	ENST00000366820.10
LEFTY2	NM_001172425.3	c.934A>G	p.Met312Val	missense_variant	5/5
LEFTY2	XM_011544266.2	c.*409A>G		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEFTY2	ENST00000366820.10	c.1036A>G	p.Met346Val	missense_variant	4/4	1	NM_003240.5	P1
	ENST00000513672.1	n.52A>G		non_coding_transcript_exon_variant	1/2	2
LEFTY2	ENST00000420304.6	c.934A>G	p.Met312Val	missense_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251300 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461740 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727172

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: 0.00000270

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	Benign	0.22
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	-0.19	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.55	.;P
Vest4		0.52
MutPred		0.88		.;Loss of ubiquitination at K350 (P = 0.0777);
MVP		0.77
MPC		0.44
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.78
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

LitVar

Other links and lift over

dbSNP: rs747778361; hg19: chr1-226125206;