rs199979438

Positions:

chr1-225939929-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_003240.5(LEFTY2):c.324G>A(p.Pro108Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,586,846 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 17 hom. )

Consequence

LEFTY2
NM_003240.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.53

Variant links:

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 links:

LEFTY2 (HGNC:):

LEFTY2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 1-225939929-C-T is Benign according to our data. Variant chr1-225939929-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.53 with no splicing effect.

BS2

High AC in GnomAd4 at 389 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEFTY2	NM_003240.5 linkuse as main transcript	c.324G>A	p.Pro108Pro	synonymous_variant	2/4	ENST00000366820.10	NP_003231.2	O00292-1A1NY82
LEFTY2	XM_011544266.2 linkuse as main transcript	c.324G>A	p.Pro108Pro	synonymous_variant	2/4		XP_011542568.1
LEFTY2	NM_001172425.3 linkuse as main transcript	c.279+45G>A		intron_variant			NP_001165896.1	O00292-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LEFTY2	ENST00000366820.10 linkuse as main transcript	c.324G>A	p.Pro108Pro	synonymous_variant	2/4	1	NM_003240.5	ENSP00000355785.5	O00292-1
LEFTY2	ENST00000420304.6 linkuse as main transcript	c.279+45G>A		intron_variant		2		ENSP00000388009.2	O00292-2
LEFTY2	ENST00000474493.1 linkuse as main transcript	n.173G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.00256

AC:

389

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00453

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00297

AC:

597

AN:

200832

Hom.:

AF XY:

0.00308

AC XY:

344

AN XY:

111548

show subpopulations

Gnomad AFR exome

AF:

0.000602

Gnomad AMR exome

AF:

0.00310

Gnomad ASJ exome

AF:

0.00222

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.00121

Gnomad NFE exome

AF:

0.00444

Gnomad OTH exome

AF:

0.00507

GnomAD4 exome

AF:

0.00353

AC:

5062

AN:

1434478

Hom.:

Cov.:

AF XY:

0.00339

AC XY:

2418

AN XY:

713026

show subpopulations

Gnomad4 AFR exome

AF:

0.000450

Gnomad4 AMR exome

AF:

0.00292

Gnomad4 ASJ exome

AF:

0.00178

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000922

Gnomad4 FIN exome

AF:

0.00125

Gnomad4 NFE exome

AF:

0.00409

Gnomad4 OTH exome

AF:

0.00349

GnomAD4 genome

AF:

0.00255

AC:

389

AN:

152368

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000673

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00453

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00312

Hom.:

Bravo

AF:

0.00252

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Left-right axis malformations

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

7.7

DANN

Benign

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over