Genetic Variant LEFTY1:p.Asp322Ala (chr1-225886863-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020997.4(LEFTY1):c.965A>C(p.Asp322Ala) variant causes a missense change. The variant allele was found at a frequency of 0.353 in 1,613,302 control chromosomes in the GnomAD database, including 103,275 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.32 ( 8293 hom., cov: 32)

Exomes 𝑓: 0.36 ( 94982 hom. )

Consequence

LEFTY1
NM_020997.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.30

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009566903).

BP6

Variant 1-225886863-T-G is Benign according to our data. Variant chr1-225886863-T-G is described in ClinVar as [Benign]. Clinvar id is 1248973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEFTY1	NM_020997.4 link	c.965A>C	p.Asp322Ala	missense_variant	Exon 4 of 4	ENST00000272134.5	NP_066277.1	O75610

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEFTY1	ENST00000272134.5 link	c.965A>C	p.Asp322Ala	missense_variant	Exon 4 of 4	1	NM_020997.4	ENSP00000272134.5		O75610
ENSG00000255835	ENST00000432920 link	c.*210A>C		3_prime_UTR_variant	Exon 8 of 8	2		ENSP00000414068.2		J3KR12

Frequencies

GnomAD3 genomes

AF:

0.316

AC:

48000

AN:

151886

Hom.:

8293

Cov.:

show subpopulations

Gnomad AFR

AF:

0.187

Gnomad AMI

AF:

0.632

Gnomad AMR

AF:

0.381

Gnomad ASJ

AF:

0.391

Gnomad EAS

AF:

0.189

Gnomad SAS

AF:

0.286

Gnomad FIN

AF:

0.432

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.364

Gnomad OTH

AF:

0.326

GnomAD3 exomes

AF:

0.345

AC:

86457

AN:

250520

Hom.:

15850

AF XY:

0.345

AC XY:

46754

AN XY:

135522

show subpopulations

Gnomad AFR exome

AF:

0.181

Gnomad AMR exome

AF:

0.418

Gnomad ASJ exome

AF:

0.399

Gnomad EAS exome

AF:

0.182

Gnomad SAS exome

AF:

0.291

Gnomad FIN exome

AF:

0.421

Gnomad NFE exome

AF:

0.366

Gnomad OTH exome

AF:

0.372

GnomAD4 exome

AF:

0.357

AC:

521381

AN:

1461298

Hom.:

94982

Cov.:

AF XY:

0.355

AC XY:

258328

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.178

Gnomad4 AMR exome

AF:

0.411

Gnomad4 ASJ exome

AF:

0.390

Gnomad4 EAS exome

AF:

0.205

Gnomad4 SAS exome

AF:

0.295

Gnomad4 FIN exome

AF:

0.410

Gnomad4 NFE exome

AF:

0.367

Gnomad4 OTH exome

AF:

0.346

GnomAD4 genome

AF:

0.316

AC:

48008

AN:

152004

Hom.:

8293

Cov.:

AF XY:

0.321

AC XY:

23852

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.187

Gnomad4 AMR

AF:

0.381

Gnomad4 ASJ

AF:

0.391

Gnomad4 EAS

AF:

0.189

Gnomad4 SAS

AF:

0.287

Gnomad4 FIN

AF:

0.432

Gnomad4 NFE

AF:

0.364

Gnomad4 OTH

AF:

0.325

Alfa

AF:

0.352

Hom.:

7618

Bravo

AF:

0.308

TwinsUK

AF:

0.368

AC:

1364

ALSPAC

AF:

0.354

AC:

1364

ESP6500AA

AF:

0.185

AC:

817

ESP6500EA

AF:

0.360

AC:

3097

ExAC

AF:

0.336

AC:

40732

Asia WGS

AF:

0.217

AC:

756

AN:

3478

EpiCase

AF:

0.372

EpiControl

AF:

0.370

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28728263) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.25

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.098

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.2

PrimateAI

Benign

0.34

PROVEAN

Benign

2.9

REVEL

Benign

0.17

Sift

Benign

1.0

Sift4G

Benign

0.67

Polyphen

0.0

Vest4

0.016

MPC

0.16

ClinPred

0.011

GERP RS

2.1

Varity_R

0.041

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over