1-225939929-C-T

Variant names:

• chr1-225939929-C-T
• rs199979438
• NM_003240.5:c.324G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.53
• Publications: 1 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 -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 Benign/Likely_benign. ClinVar VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEFTY2	NM_003240.5	MANE Select	c.324G>A	p.Pro108Pro	synonymous	Exon 2 of 4	NP_003231.2
	LEFTY2	NM_001172425.3		c.279+45G>A		intron	N/A	NP_001165896.1	O00292-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEFTY2	ENST00000366820.10	TSL:1 MANE Select	c.324G>A	p.Pro108Pro	synonymous	Exon 2 of 4	ENSP00000355785.5	O00292-1
	LEFTY2	ENST00000420304.6	TSL:2	c.279+45G>A		intron	N/A	ENSP00000388009.2	O00292-2
	LEFTY2	ENST00000474493.1	TSL:3	n.173G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 389 AN: 152250 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.00297 AC: 597 AN: 200832 AF XY: 0.00308

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 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.: 17 Cov.: 34 AF XY: 0.00339 AC XY: 2418 AN XY: 713026

African (AFR) AF: 0.000450 AC: 15 AN: 33332

American (AMR) AF: 0.00292 AC: 126 AN: 43178

Ashkenazi Jewish (ASJ) AF: 0.00178 AC: 46 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39406

South Asian (SAS) AF: 0.000922 AC: 78 AN: 84578

European-Finnish (FIN) AF: 0.00125 AC: 46 AN: 36692

Middle Eastern (MID) AF: 0.00436 AC: 18 AN: 4124

European-Non Finnish (NFE) AF: 0.00409 AC: 4525 AN: 1107706

Other (OTH) AF: 0.00349 AC: 208 AN: 59642

GnomAD4 genome AF: 0.00255 AC: 389 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.00250 AC XY: 186 AN XY: 74506

African (AFR) AF: 0.000673 AC: 28 AN: 41600

American (AMR) AF: 0.00189 AC: 29 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00252

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Left-right axis malformations (2)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	7.7
DANN	Benign	0.94
PhyloP100		-1.5
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: rs199979438; hg19: chr1-226127629; COSMIC: COSV64746800; COSMIC: COSV64746800;