1-225894725-A-G

Variant names:

• chr1-225894725-A-G
• rs1223245
• ENST00000432920.2:c.576-6693T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000432920.2(ENSG00000255835):​c.576-6693T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 152,120 control chromosomes in the GnomAD database, including 8,240 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (8240 hom., cov: 32)
• Consequence: ENSG00000255835 ENST00000432920.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.240
• Publications: 9 publications found

Genes affected

ENSG00000255835 (HGNC:):

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000255835	ENST00000432920.2	c.576-6693T>C		intron_variant	Intron 5 of 7	2		ENSP00000414068.2
LEFTY1	ENST00000492457.1	n.265-6693T>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47751 AN: 152002 Hom.: 8238 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.323

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.314 AC: 47759 AN: 152120 Hom.: 8240 Cov.: 32 AF XY: 0.319 AC XY: 23700 AN XY: 74356

African (AFR) AF: 0.183 AC: 7616 AN: 41518

American (AMR) AF: 0.380 AC: 5807 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1358 AN: 3468

East Asian (EAS) AF: 0.184 AC: 953 AN: 5176

South Asian (SAS) AF: 0.267 AC: 1289 AN: 4826

European-Finnish (FIN) AF: 0.431 AC: 4551 AN: 10566

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

European-Non Finnish (NFE) AF: 0.365 AC: 24787 AN: 67970

Other (OTH) AF: 0.321 AC: 678 AN: 2110

Alfa AF: 0.347 Hom.: 9592

Bravo AF: 0.306

Asia WGS AF: 0.198 AC: 691 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.5
DANN	Benign	0.89
PhyloP100		0.24

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: rs1223245; hg19: chr1-226082425; COSMIC: COSV71540550;