rs149969900

Variant names:

• chr1-225937768-G-A
• rs149969900
• NM_003240.5:c.774C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003240.5(LEFTY2):​c.774C>T​(p.Thr258Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,611,442 control chromosomes in the GnomAD database, including 279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (121 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (158 hom.)
• Consequence: LEFTY2 NM_003240.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.01
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-225937768-G-A is Benign according to our data. Variant chr1-225937768-G-A is described in ClinVar as Benign. ClinVar VariationId is 138109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0828 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.774C>T	p.Thr258Thr	synonymous	Exon 4 of 4	NP_003231.2
	LEFTY2	NM_001172425.3		c.672C>T	p.Thr224Thr	synonymous	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.774C>T	p.Thr258Thr	synonymous	Exon 4 of 4	ENSP00000355785.5	O00292-1
	LEFTY2	ENST00000420304.6	TSL:2	c.672C>T	p.Thr224Thr	synonymous	Exon 5 of 5	ENSP00000388009.2	O00292-2
	ENSG00000248322	ENST00000513672.1	TSL:2	n.-211C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0255 AC: 3882 AN: 152100 Hom.: 122 Cov.: 32

Gnomad AFR AF: 0.0852

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00810 AC: 1999 AN: 246876 AF XY: 0.00617

Gnomad AFR exome AF: 0.0898

Gnomad AMR exome AF: 0.00619

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000682

Gnomad OTH exome AF: 0.00720

GnomAD4 exome AF: 0.00337 AC: 4922 AN: 1459224 Hom.: 158 Cov.: 29 AF XY: 0.00299 AC XY: 2171 AN XY: 725630

African (AFR) AF: 0.0901 AC: 3011 AN: 33430

American (AMR) AF: 0.00662 AC: 295 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 619 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00566 AC: 32 AN: 5658

European-Non Finnish (NFE) AF: 0.000426 AC: 473 AN: 1110412

Other (OTH) AF: 0.00797 AC: 480 AN: 60230

GnomAD4 genome AF: 0.0255 AC: 3889 AN: 152218 Hom.: 121 Cov.: 32 AF XY: 0.0250 AC XY: 1857 AN XY: 74418

African (AFR) AF: 0.0851 AC: 3534 AN: 41510

American (AMR) AF: 0.0101 AC: 155 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68020

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0153 Hom.: 23

Bravo AF: 0.0294

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Left-right axis malformations (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.60
PhyloP100		-1.0
Mutation Taster		=100/0	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: rs149969900; hg19: chr1-226125468;