Genetic Variant NM_020997.4:c.902C>A (chr1-225886926-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020997.4(LEFTY1):c.902C>A(p.Pro301Gln) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P301L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

LEFTY1
NM_020997.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.269

Publications

0 publications found

Variant links:

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]

LEFTY1 links:

ENSG00000255835 (HGNC:):

ENSG00000255835 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2179285).

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.902C>A	p.Pro301Gln	missense	Exon 4 of 4	NP_066277.1	O75610

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LEFTY1	ENST00000272134.5	TSL:1 MANE Select	c.902C>A	p.Pro301Gln	missense	Exon 4 of 4	ENSP00000272134.5	O75610
ENSG00000255835	ENST00000432920.2	TSL:2	c.*147C>A		3_prime_UTR	Exon 8 of 8	ENSP00000414068.2	J3KR12
LEFTY1	ENST00000946628.1		c.926C>A	p.Pro309Gln	missense	Exon 4 of 4	ENSP00000616687.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248530

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.64

M_CAP

Benign

0.055

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.9

PhyloP100

0.27

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.098

Sift

Benign

0.075

Sift4G

Uncertain

0.015

Polyphen

0.52

Vest4

0.18

MutPred

0.60

Loss of catalytic residue at P300 (P = 0.0175)

MVP

0.69

MPC

0.16

ClinPred

0.37

GERP RS

0.67

Varity_R

0.086

gMVP

0.58

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over