1-225939743-G-T

Variant names:

• chr1-225939743-G-T
• rs74578461
• NM_003240.5:c.497+13C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003240.5(LEFTY2):​c.497+13C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LEFTY2 NM_003240.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEFTY2	NM_003240.5	c.497+13C>A		intron_variant	Intron 2 of 3	ENST00000366820.10	NP_003231.2
LEFTY2	NM_001172425.3	c.395+13C>A		intron_variant	Intron 3 of 4		NP_001165896.1
LEFTY2	XM_011544266.2	c.497+13C>A		intron_variant	Intron 2 of 3		XP_011542568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEFTY2	ENST00000366820.10	c.497+13C>A		intron_variant	Intron 2 of 3	1	NM_003240.5	ENSP00000355785.5
LEFTY2	ENST00000420304.6	c.395+13C>A		intron_variant	Intron 3 of 4	2		ENSP00000388009.2
LEFTY2	ENST00000474493.1	n.346+13C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445994 Hom.: 0 Cov.: 65 AF XY: 0.00 AC XY: 0 AN XY: 718732

African (AFR) AF: 0.00 AC: 0 AN: 33086

American (AMR) AF: 0.00 AC: 0 AN: 42368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25836

East Asian (EAS) AF: 0.00 AC: 0 AN: 39346

South Asian (SAS) AF: 0.00 AC: 0 AN: 85512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4412

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106482

Other (OTH) AF: 0.00 AC: 0 AN: 59628

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.065
DANN	Benign	0.93
PhyloP100		-1.7

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: rs74578461; hg19: chr1-226127443;