1-225887409-C-A

Variant names:

• chr1-225887409-C-A
• NM_020997.4:c.727G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020997.4(LEFTY1):​c.727G>T​(p.Gly243Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LEFTY1 NM_020997.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

Genes affected

LEFTY1 (HGNC:6552): (left-right determination factor 1) 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. This gene is closely linked to both a related family member and a related pseudogene. [provided by RefSeq, Aug 2016]

ENSG00000255835 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23664221).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEFTY1	NM_020997.4	c.727G>T	p.Gly243Trp	missense_variant	Exon 3 of 4	ENST00000272134.5	NP_066277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEFTY1	ENST00000272134.5	c.727G>T	p.Gly243Trp	missense_variant	Exon 3 of 4	1	NM_020997.4	ENSP00000272134.5
ENSG00000255835	ENST00000432920.2	c.1052G>T	p.Trp351Leu	missense_variant	Exon 7 of 8	2		ENSP00000414068.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.727G>T (p.G243W) alteration is located in exon 3 (coding exon 3) of the LEFTY1 gene. This alteration results from a G to T substitution at nucleotide position 727, causing the glycine (G) at amino acid position 243 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.25
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.016	D
Polyphen		0.74	P
Vest4		0.17
MutPred		0.47		Loss of disorder (P = 8e-04);
MVP		0.37
MPC		0.20
ClinPred		0.20	T
GERP RS		-8.3
Varity_R		0.090
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-226075109;