chr1-225941087-G-T

Variant names:

• chr1-225941087-G-T
• rs370508860
• NM_003240.5:c.54C>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003240.5(LEFTY2):​c.54C>A​(p.Pro18Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,595,954 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. Synonymous variant affecting the same amino acid position (i.e. P18P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LEFTY2 NM_003240.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP7: Synonymous conserved (PhyloP=-1.56 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEFTY2	NM_003240.5	c.54C>A	p.Pro18Pro	synonymous_variant	Exon 1 of 4	ENST00000366820.10	NP_003231.2
LEFTY2	NM_001172425.3	c.54C>A	p.Pro18Pro	synonymous_variant	Exon 1 of 5		NP_001165896.1
LEFTY2	XM_011544266.2	c.54C>A	p.Pro18Pro	synonymous_variant	Exon 1 of 4		XP_011542568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEFTY2	ENST00000366820.10	c.54C>A	p.Pro18Pro	synonymous_variant	Exon 1 of 4	1	NM_003240.5	ENSP00000355785.5
LEFTY2	ENST00000420304.6	c.54C>A	p.Pro18Pro	synonymous_variant	Exon 1 of 5	2		ENSP00000388009.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443748 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 716520

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.46

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: rs370508860; hg19: chr1-226128787;