1-225937768-G-A

Position:

chr1-225937768-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003240.5(LEFTY2):c.774C>T(p.Thr258=) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.01

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 138109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225937768-G-A is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LEFTY2	NM_003240.5 linkuse as main transcript	c.774C>T	p.Thr258=	synonymous_variant	4/4	ENST00000366820.10	NP_003231.2
LEFTY2	NM_001172425.3 linkuse as main transcript	c.672C>T	p.Thr224=	synonymous_variant	5/5		NP_001165896.1
LEFTY2	XM_011544266.2 linkuse as main transcript	c.*147C>T		3_prime_UTR_variant	4/4		XP_011542568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEFTY2	ENST00000366820.10 linkuse as main transcript	c.774C>T	p.Thr258=	synonymous_variant	4/4	1	NM_003240.5	ENSP00000355785	P1	O00292-1
LEFTY2	ENST00000420304.6 linkuse as main transcript	c.672C>T	p.Thr224=	synonymous_variant	5/5	2		ENSP00000388009		O00292-2

Frequencies

GnomAD3 genomes

AF:

0.0255

AC:

3882

AN:

152100

Hom.:

122

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00810

AC:

1999

AN:

246876

Hom.:

AF XY:

0.00617

AC XY:

826

AN XY:

133792

show subpopulations

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 SAS exome

AF:

0.0000993

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.:

AF XY:

0.00299

AC XY:

2171

AN XY:

725630

show subpopulations

Gnomad4 AFR exome

AF:

0.0901

Gnomad4 AMR exome

AF:

0.00662

Gnomad4 ASJ exome

AF:

0.0238

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000426

Gnomad4 OTH exome

AF:

0.00797

GnomAD4 genome

AF:

0.0255

AC:

3889

AN:

152218

Hom.:

121

Cov.:

AF XY:

0.0250

AC XY:

1857

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0851

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.0282

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.0153

Hom.:

Bravo

AF:

0.0294

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2017	- -

Left-right axis malformations

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 29, 2024	- -

not provided

Benign:1

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

-0.81

CADD

Benign

2.6

DANN

Benign

0.60

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