rs61731738

Positions:

• chr1-225937560-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003240.5(LEFTY2):​c.982G>A​(p.Val328Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00707 in 1,613,990 control chromosomes in the GnomAD database, including 683 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (364 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (319 hom.)
• Consequence: LEFTY2 NM_003240.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.40

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]

ENSG00000248322 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016655624).
• BP6: Variant 1-225937560-C-T is Benign according to our data. Variant chr1-225937560-C-T is described in ClinVar as [Benign]. Clinvar id is 138111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225937560-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEFTY2	NM_003240.5	c.982G>A	p.Val328Ile	missense_variant	4/4	ENST00000366820.10	NP_003231.2
LEFTY2	NM_001172425.3	c.880G>A	p.Val294Ile	missense_variant	5/5		NP_001165896.1
LEFTY2	XM_011544266.2	c.*355G>A		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	c.982G>A	p.Val328Ile	missense_variant	4/4	1	NM_003240.5	ENSP00000355785.5
LEFTY2	ENST00000420304.6	c.880G>A	p.Val294Ile	missense_variant	5/5	2		ENSP00000388009.2
ENSG00000248322	ENST00000513672.1	n.-3G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 5721 AN: 152116 Hom.: 363 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.00974 AC: 2448 AN: 251242 Hom.: 160 AF XY: 0.00695 AC XY: 945 AN XY: 135874

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000634

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00389 AC: 5682 AN: 1461756 Hom.: 319 Cov.: 29 AF XY: 0.00333 AC XY: 2418 AN XY: 727176

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.00646

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000319

Gnomad4 OTH exome AF: 0.00818

GnomAD4 genome AF: 0.0376 AC: 5731 AN: 152234 Hom.: 364 Cov.: 32 AF XY: 0.0361 AC XY: 2687 AN XY: 74438

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0176 Hom.: 67

Bravo AF: 0.0432

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.122 AC: 539

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0122 AC: 1485

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00124

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2012	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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. -

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
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.22	N;N
REVEL	Benign	0.21
Sift	Benign	0.28	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.98	.;D
Vest4		0.035
MPC		0.26
ClinPred		0.025	T
GERP RS		2.0
Varity_R		0.065
gMVP		0.67

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: rs61731738; hg19: chr1-226125260;