1-225937685-G-A

Variant names:

• chr1-225937685-G-A
• rs2295418
• NM_003240.5:c.857C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003240.5(LEFTY2):​c.857C>T​(p.Pro286Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,613,636 control chromosomes in the GnomAD database, including 1,509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P286P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.030 (113 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1396 hom.)
• Consequence: LEFTY2 NM_003240.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 9.45
• Publications: 19 publications found

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]

LEFTY2 Gene-Disease associations (from GenCC):

• visceral heterotaxy

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000248322 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052312613).
• BP6: Variant 1-225937685-G-A is Benign according to our data. Variant chr1-225937685-G-A is described in ClinVar as Benign. ClinVar VariationId is 138110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003240.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEFTY2	NM_003240.5	MANE Select	c.857C>T	p.Pro286Leu	missense	Exon 4 of 4	NP_003231.2
	LEFTY2	NM_001172425.3		c.755C>T	p.Pro252Leu	missense	Exon 5 of 5	NP_001165896.1	O00292-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEFTY2	ENST00000366820.10	TSL:1 MANE Select	c.857C>T	p.Pro286Leu	missense	Exon 4 of 4	ENSP00000355785.5	O00292-1
	LEFTY2	ENST00000420304.6	TSL:2	c.755C>T	p.Pro252Leu	missense	Exon 5 of 5	ENSP00000388009.2	O00292-2
	ENSG00000248322	ENST00000513672.1	TSL:2	n.-128C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4500 AN: 152194 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.00861

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0384

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0770

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0339

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0408 AC: 10210 AN: 250250 AF XY: 0.0419

Gnomad AFR exome AF: 0.00743

Gnomad AMR exome AF: 0.0404

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.100

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0361

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0384 AC: 56147 AN: 1461324 Hom.: 1396 Cov.: 30 AF XY: 0.0391 AC XY: 28423 AN XY: 726868

African (AFR) AF: 0.00729 AC: 244 AN: 33462

American (AMR) AF: 0.0411 AC: 1839 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 463 AN: 26124

East Asian (EAS) AF: 0.123 AC: 4868 AN: 39682

South Asian (SAS) AF: 0.0633 AC: 5463 AN: 86238

European-Finnish (FIN) AF: 0.0207 AC: 1105 AN: 53390

Middle Eastern (MID) AF: 0.0176 AC: 101 AN: 5748

European-Non Finnish (NFE) AF: 0.0357 AC: 39703 AN: 1111622

Other (OTH) AF: 0.0391 AC: 2361 AN: 60354

GnomAD4 genome AF: 0.0295 AC: 4500 AN: 152312 Hom.: 113 Cov.: 32 AF XY: 0.0298 AC XY: 2217 AN XY: 74482

African (AFR) AF: 0.00858 AC: 357 AN: 41586

American (AMR) AF: 0.0383 AC: 586 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3470

East Asian (EAS) AF: 0.112 AC: 578 AN: 5176

South Asian (SAS) AF: 0.0773 AC: 373 AN: 4826

European-Finnish (FIN) AF: 0.0164 AC: 174 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0339 AC: 2308 AN: 68022

Other (OTH) AF: 0.0322 AC: 68 AN: 2114

Alfa AF: 0.0210 Hom.: 9

Bravo AF: 0.0291

TwinsUK AF: 0.0291 AC: 108

ALSPAC AF: 0.0340 AC: 131

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.0341 AC: 293

ExAC AF: 0.0413 AC: 5020

Asia WGS AF: 0.103 AC: 359 AN: 3478

EpiCase AF: 0.0292

EpiControl AF: 0.0324

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Left-right axis malformations (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.5
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.23
MPC		0.45
ClinPred		0.039	T
GERP RS		4.2
Varity_R		0.41
gMVP		0.79
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2295418; hg19: chr1-226125385; COSMIC: COSV107471909;