1-225937639-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_003240.5(LEFTY2):c.903G>A(p.Pro301=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,614,100 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (6 hom.)
• Consequence: LEFTY2 NM_003240.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.846

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-225937639-C-T is Benign according to our data. Variant chr1-225937639-C-T is described in ClinVar as [Benign]. Clinvar id is 414130.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-225937639-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.846 with no splicing effect.
• BS2: High AC in GnomAd at 216 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEFTY2	NM_003240.5	c.903G>A	p.Pro301=	synonymous_variant	4/4	ENST00000366820.10
LEFTY2	NM_001172425.3	c.801G>A	p.Pro267=	synonymous_variant	5/5
LEFTY2	XM_011544266.2	c.*276G>A		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEFTY2	ENST00000366820.10	c.903G>A	p.Pro301=	synonymous_variant	4/4	1	NM_003240.5	P1
LEFTY2	ENST00000420304.6	c.801G>A	p.Pro267=	synonymous_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00470

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000504 AC: 126 AN: 249792 Hom.: 0 AF XY: 0.000355 AC XY: 48 AN XY: 135378

Gnomad AFR exome AF: 0.00572

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000984

GnomAD4 exome AF: 0.000289 AC: 422 AN: 1461768 Hom.: 6 Cov.: 29 AF XY: 0.000276 AC XY: 201 AN XY: 727196

Gnomad4 AFR exome AF: 0.00612

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000656

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.00140 AC: 214 AN: 152332 Hom.: 1 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74492

Gnomad4 AFR AF: 0.00467

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000622 Hom.: 0

Bravo AF: 0.00176

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Left-right axis malformations Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	1.2
Dann	Benign	0.86

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: rs61731739; hg19: chr1-226125339;