chr1-225936945-A-C

Variant names:

• chr1-225936945-A-C
• rs6697182
• NM_003240.5:c.*496T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003240.5(LEFTY2):​c.*496T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 168,312 control chromosomes in the GnomAD database, including 370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.038 (369 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (1 hom.)
• Consequence: LEFTY2 NM_003240.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0950
• Publications: 1 publications found

Genes affected

LEFTY2 (HGNC:3122): (left-right determination factor 2) 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. The protein may also play a role in endometrial bleeding. Mutations in this gene have been associated with left-right axis malformations, particularly in the heart and lungs. Some types of infertility have been associated with dysregulated expression of this gene in the endometrium. This gene is closely linked to both a related family member and a related pseudogene. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

LEFTY2 Gene-Disease associations (from GenCC):

• visceral heterotaxy

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000248322 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-225936945-A-C is Benign according to our data. Variant chr1-225936945-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 295962.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003240.5. 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
	LEFTY2	NM_003240.5	MANE Select	c.*496T>G		3_prime_UTR	Exon 4 of 4	NP_003231.2
	LEFTY2	NM_001172425.3		c.*496T>G		3_prime_UTR	Exon 5 of 5	NP_001165896.1	O00292-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEFTY2	ENST00000366820.10	TSL:1 MANE Select	c.*496T>G		3_prime_UTR	Exon 4 of 4	ENSP00000355785.5	O00292-1
	LEFTY2	ENST00000420304.6	TSL:2	c.*496T>G		3_prime_UTR	Exon 5 of 5	ENSP00000388009.2	O00292-2
	ENSG00000248322	ENST00000513672.1	TSL:2	n.176-368T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0378 AC: 5754 AN: 152130 Hom.: 367 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0272

GnomAD4 exome AF: 0.00224 AC: 36 AN: 16064 Hom.: 1 Cov.: 0 AF XY: 0.00184 AC XY: 16 AN XY: 8694

African (AFR) AF: 0.101 AC: 17 AN: 168

American (AMR) AF: 0.00610 AC: 12 AN: 1968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 242

East Asian (EAS) AF: 0.00 AC: 0 AN: 620

South Asian (SAS) AF: 0.00 AC: 0 AN: 2174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 28

European-Non Finnish (NFE) AF: 0.000518 AC: 5 AN: 9646

Other (OTH) AF: 0.00288 AC: 2 AN: 694

GnomAD4 genome AF: 0.0379 AC: 5765 AN: 152248 Hom.: 369 Cov.: 32 AF XY: 0.0362 AC XY: 2696 AN XY: 74448

African (AFR) AF: 0.131 AC: 5460 AN: 41522

American (AMR) AF: 0.0133 AC: 203 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68010

Other (OTH) AF: 0.0269 AC: 57 AN: 2116

Alfa AF: 0.0188 Hom.: 98

Bravo AF: 0.0434

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Left-right axis malformations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.8
DANN	Benign	0.83
PhyloP100		0.095
Mutation Taster		=100/0	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: rs6697182; hg19: chr1-226124645;