1-225937144-T-A

Variant names:

• chr1-225937144-T-A
• rs80180076
• NM_003240.5:c.*297A>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003240.5(LEFTY2):​c.*297A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 532,948 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: LEFTY2 NM_003240.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.539
• 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

ENSG00000248322 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BS2: High AC in GnomAd4 at 28 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.*297A>T		3_prime_UTR	Exon 4 of 4	NP_003231.2
	LEFTY2	NM_001172425.3		c.*297A>T		3_prime_UTR	Exon 5 of 5	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.*297A>T		3_prime_UTR	Exon 4 of 4	ENSP00000355785.5	O00292-1
	LEFTY2	ENST00000420304.6	TSL:2	c.*297A>T		3_prime_UTR	Exon 5 of 5	ENSP00000388009.2	O00292-2
	ENSG00000248322	ENST00000513672.1	TSL:2	n.175+239A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000187 AC: 71 AN: 380628 Hom.: 1 Cov.: 3 AF XY: 0.000139 AC XY: 28 AN XY: 200830

African (AFR) AF: 0.000273 AC: 3 AN: 11006

American (AMR) AF: 0.00 AC: 0 AN: 16286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11806

East Asian (EAS) AF: 0.00212 AC: 52 AN: 24486

South Asian (SAS) AF: 0.00 AC: 0 AN: 43226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1636

European-Non Finnish (NFE) AF: 0.0000132 AC: 3 AN: 227372

Other (OTH) AF: 0.000586 AC: 13 AN: 22172

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74486

African (AFR) AF: 0.000168 AC: 7 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000185

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-0.71
CADD	Benign	5.1
DANN	Benign	0.88
PhyloP100		0.54

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: rs80180076; hg19: chr1-226124844;