rs146485828

Variant names:

• chr1-225886993-C-T
• rs146485828
• NM_020997.4:c.835G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-225886993-C-T
• chr1-225886993-C-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020997.4(LEFTY1):​c.835G>A​(p.Glu279Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00255 in 1,609,652 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E279D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (49 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (50 hom.)
• Consequence: LEFTY1 NM_020997.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.30
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030772388).
• BP6: Variant 1-225886993-C-T is Benign according to our data. Variant chr1-225886993-C-T is described in ClinVar as Benign. ClinVar VariationId is 791837.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1970/152328) while in subpopulation AFR AF = 0.0453 (1884/41582). AF 95% confidence interval is 0.0436. There are 49 homozygotes in GnomAd4. There are 916 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1970 AD gene.

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.835G>A	p.Glu279Lys	missense	Exon 4 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.835G>A	p.Glu279Lys	missense	Exon 4 of 4	ENSP00000272134.5	O75610
	ENSG00000255835	ENST00000432920.2	TSL:2	c.*80G>A		3_prime_UTR	Exon 8 of 8	ENSP00000414068.2	J3KR12
	LEFTY1	ENST00000946628.1		c.859G>A	p.Glu287Lys	missense	Exon 4 of 4	ENSP00000616687.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1964 AN: 152210 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0453

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00345 AC: 855 AN: 248112 AF XY: 0.00246

Gnomad AFR exome AF: 0.0466

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00147 AC: 2140 AN: 1457324 Hom.: 50 Cov.: 34 AF XY: 0.00126 AC XY: 914 AN XY: 724290

African (AFR) AF: 0.0503 AC: 1677 AN: 33364

American (AMR) AF: 0.00281 AC: 125 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.000349 AC: 30 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53194

Middle Eastern (MID) AF: 0.00175 AC: 10 AN: 5720

European-Non Finnish (NFE) AF: 0.0000929 AC: 103 AN: 1108946

Other (OTH) AF: 0.00324 AC: 195 AN: 60146

GnomAD4 genome AF: 0.0129 AC: 1970 AN: 152328 Hom.: 49 Cov.: 33 AF XY: 0.0123 AC XY: 916 AN XY: 74486

African (AFR) AF: 0.0453 AC: 1884 AN: 41582

American (AMR) AF: 0.00399 AC: 61 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00155 Hom.: 2

Bravo AF: 0.0149

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00432 AC: 524

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.3
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.13
Sift	Benign	0.23	T
Sift4G	Benign	0.066	T
Polyphen		0.014	B
Vest4		0.14
MVP		0.58
MPC		0.14
ClinPred		0.071	T
GERP RS		3.0
Varity_R		0.16
gMVP		0.74
Mutation Taster		=96/4	polymorphism

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: rs146485828; hg19: chr1-226074693; COSMIC: COSV55283798; COSMIC: COSV55283798;