1-225886863-T-G

Variant names:

• chr1-225886863-T-G
• rs360057
• NM_020997.4:c.965A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8293 hom., cov: 32)
  • Exomes 𝑓: 0.36 (94982 hom.)
• Consequence: LEFTY1 NM_020997.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.30
• Publications: 28 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: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEFTY1	NM_020997.4	MANE Select	c.965A>C	p.Asp322Ala	missense	Exon 4 of 4	NP_066277.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEFTY1	ENST00000272134.5	TSL:1 MANE Select	c.965A>C	p.Asp322Ala	missense	Exon 4 of 4	ENSP00000272134.5
	ENSG00000255835	ENST00000432920.2	TSL:2	c.*210A>C		3_prime_UTR	Exon 8 of 8	ENSP00000414068.2

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48000 AN: 151886 Hom.: 8293 Cov.: 32

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

GnomAD2 exomes AF: 0.345 AC: 86457 AN: 250520 AF XY: 0.345

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 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.: 82 AF XY: 0.355 AC XY: 258328 AN XY: 726936

African (AFR) AF: 0.178 AC: 5963 AN: 33476

American (AMR) AF: 0.411 AC: 18378 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10200 AN: 26128

East Asian (EAS) AF: 0.205 AC: 8152 AN: 39686

South Asian (SAS) AF: 0.295 AC: 25434 AN: 86250

European-Finnish (FIN) AF: 0.410 AC: 21785 AN: 53196

Middle Eastern (MID) AF: 0.427 AC: 2397 AN: 5620

European-Non Finnish (NFE) AF: 0.367 AC: 408203 AN: 1111886

Other (OTH) AF: 0.346 AC: 20869 AN: 60380

GnomAD4 genome AF: 0.316 AC: 48008 AN: 152004 Hom.: 8293 Cov.: 32 AF XY: 0.321 AC XY: 23852 AN XY: 74282

African (AFR) AF: 0.187 AC: 7735 AN: 41442

American (AMR) AF: 0.381 AC: 5828 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1356 AN: 3466

East Asian (EAS) AF: 0.189 AC: 979 AN: 5168

South Asian (SAS) AF: 0.287 AC: 1379 AN: 4812

European-Finnish (FIN) AF: 0.432 AC: 4567 AN: 10564

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24758 AN: 67956

Other (OTH) AF: 0.325 AC: 685 AN: 2108

Alfa AF: 0.348 Hom.: 11420

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

Submissions by phenotype

not provided Benign:2

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)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.63
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.098	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.2	N
PhyloP100		6.3
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.9	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.016
MPC		0.16
ClinPred		0.011	T
GERP RS		2.1
Varity_R		0.041
gMVP		0.54
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs360057; hg19: chr1-226074563; COSMIC: COSV55282479; COSMIC: COSV55282479;