rs429477

Variant names:

• chr1-225939828-T-C
• rs429477
• NM_003240.5:c.425A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003240.5(LEFTY2):​c.425A>G​(p.Gln142Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,548,888 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q142E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (20 hom.)
• Consequence: LEFTY2 NM_003240.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.121
• Publications: 1 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047640204).
• BP6: Variant 1-225939828-T-C is Benign according to our data. Variant chr1-225939828-T-C is described in ClinVar as Benign. ClinVar VariationId is 295971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00238 (362/152308) while in subpopulation EAS AF = 0.0288 (149/5176). AF 95% confidence interval is 0.025. There are 2 homozygotes in GnomAd4. There are 224 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 362 AD gene.

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.425A>G	p.Gln142Arg	missense	Exon 2 of 4	NP_003231.2
	LEFTY2	NM_001172425.3		c.323A>G	p.Gln108Arg	missense	Exon 3 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.425A>G	p.Gln142Arg	missense	Exon 2 of 4	ENSP00000355785.5	O00292-1
	LEFTY2	ENST00000420304.6	TSL:2	c.323A>G	p.Gln108Arg	missense	Exon 3 of 5	ENSP00000388009.2	O00292-2
	LEFTY2	ENST00000474493.1	TSL:3	n.274A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152190 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.0293

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00724

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00235 AC: 347 AN: 147496 AF XY: 0.00225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000516

Gnomad ASJ exome AF: 0.000489

Gnomad EAS exome AF: 0.0186

Gnomad FIN exome AF: 0.00517

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00146 AC: 2044 AN: 1396580 Hom.: 20 Cov.: 34 AF XY: 0.00151 AC XY: 1043 AN XY: 690280

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000216 AC: 7 AN: 32446

American (AMR) AF: 0.000440 AC: 16 AN: 36366

Ashkenazi Jewish (ASJ) AF: 0.000517 AC: 13 AN: 25136

East Asian (EAS) AF: 0.0233 AC: 860 AN: 36934

South Asian (SAS) AF: 0.00230 AC: 185 AN: 80608

European-Finnish (FIN) AF: 0.00741 AC: 283 AN: 38180

Middle Eastern (MID) AF: 0.00123 AC: 5 AN: 4064

European-Non Finnish (NFE) AF: 0.000479 AC: 520 AN: 1084826

Other (OTH) AF: 0.00267 AC: 155 AN: 58020

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152308 Hom.: 2 Cov.: 33 AF XY: 0.00301 AC XY: 224 AN XY: 74480

African (AFR) AF: 0.000505 AC: 21 AN: 41550

American (AMR) AF: 0.000784 AC: 12 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.0288 AC: 149 AN: 5176

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4830

European-Finnish (FIN) AF: 0.00724 AC: 77 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68022

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00223 Hom.: 0

Bravo AF: 0.00179

ExAC AF: 0.000844 AC: 89

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Left-right axis malformations (2)
-	-	1	LEFTY2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.7
DANN	Benign	0.44
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.060	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.5	N
PhyloP100		-0.12
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.041
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.39
MPC		1.4
ClinPred		0.0063	T
GERP RS		-0.80
Varity_R		0.056
gMVP		0.57
Mutation Taster		=99/1	polymorphism

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: rs429477; hg19: chr1-226127528; COSMIC: COSV107471912; COSMIC: COSV107471912;