1-225939905-G-C

Variant names:

• chr1-225939905-G-C
• rs755946624
• NM_003240.5:c.348C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_003240.5(LEFTY2):​c.348C>G​(p.Ala116Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 1,413,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A116A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: LEFTY2 NM_003240.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.69
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-225939905-G-C is Benign according to our data. Variant chr1-225939905-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2882097.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.69 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEFTY2	NM_003240.5	MANE Select	c.348C>G	p.Ala116Ala	synonymous	Exon 2 of 4	NP_003231.2
	LEFTY2	NM_001172425.3		c.280-34C>G		intron	N/A	NP_001165896.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEFTY2	ENST00000366820.10	TSL:1 MANE Select	c.348C>G	p.Ala116Ala	synonymous	Exon 2 of 4	ENSP00000355785.5
	LEFTY2	ENST00000474493.1	TSL:3	n.197C>G		non_coding_transcript_exon	Exon 1 of 2
	LEFTY2	ENST00000420304.6	TSL:2	c.280-34C>G		intron	N/A	ENSP00000388009.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000127 AC: 2 AN: 157386 AF XY: 0.0000115

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000153

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.00000637 AC: 9 AN: 1413808 Hom.: 0 Cov.: 34 AF XY: 0.00000714 AC XY: 5 AN XY: 700690

African (AFR) AF: 0.0000303 AC: 1 AN: 33056

American (AMR) AF: 0.0000256 AC: 1 AN: 39116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25412

East Asian (EAS) AF: 0.00 AC: 0 AN: 38560

South Asian (SAS) AF: 0.00 AC: 0 AN: 82460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35344

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4102

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1096838

Other (OTH) AF: 0.0000509 AC: 3 AN: 58920

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Left-right axis malformations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.46
DANN	Benign	0.77
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

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: rs755946624; hg19: chr1-226127605;