1-225887412-G-A

Variant names:

• chr1-225887412-G-A
• NM_020997.4:c.724C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020997.4(LEFTY1):​c.724C>T​(p.Leu242Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.20
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020997.4. 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
	LEFTY1	NM_020997.4	MANE Select	c.724C>T	p.Leu242Phe	missense	Exon 3 of 4	NP_066277.1	O75610

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEFTY1	ENST00000272134.5	TSL:1 MANE Select	c.724C>T	p.Leu242Phe	missense	Exon 3 of 4	ENSP00000272134.5	O75610
	ENSG00000255835	ENST00000432920.2	TSL:2	c.1049C>T	p.Pro350Leu	missense	Exon 7 of 8	ENSP00000414068.2	J3KR12
	LEFTY1	ENST00000946628.1		c.748C>T	p.Leu250Phe	missense	Exon 3 of 4	ENSP00000616687.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.16
MutPred		0.60		Gain of catalytic residue at L242 (P = 0.0135)
MVP		0.89
MPC		0.36
ClinPred		0.92	D
GERP RS		3.2
Varity_R		0.22
gMVP		0.58
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr1-226075112;