rs74578461

Variant names:

• chr1-225939743-G-C
• rs74578461
• NM_003240.5:c.497+13C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-225939743-G-C
• chr1-225939743-G-T

Variant summary

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

The NM_003240.5(LEFTY2):​c.497+13C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,597,580 control chromosomes in the GnomAD database, including 76,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8009 hom., cov: 34)
  • Exomes 𝑓: 0.31 (68855 hom.)
• Consequence: LEFTY2 NM_003240.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.70
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-225939743-G-C is Benign according to our data. Variant chr1-225939743-G-C is described in ClinVar as Benign. ClinVar VariationId is 138108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.363 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.497+13C>G		intron	N/A	NP_003231.2
	LEFTY2	NM_001172425.3		c.395+13C>G		intron	N/A	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.497+13C>G		intron	N/A	ENSP00000355785.5	O00292-1
	LEFTY2	ENST00000420304.6	TSL:2	c.395+13C>G		intron	N/A	ENSP00000388009.2	O00292-2
	LEFTY2	ENST00000474493.1	TSL:3	n.346+13C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49063 AN: 151748 Hom.: 8009 Cov.: 34

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.337

GnomAD2 exomes AF: 0.311 AC: 65247 AN: 210088 AF XY: 0.304

Gnomad AFR exome AF: 0.362

Gnomad AMR exome AF: 0.420

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.143

Gnomad FIN exome AF: 0.326

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.307 AC: 443228 AN: 1445714 Hom.: 68855 Cov.: 65 AF XY: 0.303 AC XY: 218021 AN XY: 718570

African (AFR) AF: 0.353 AC: 11660 AN: 33076

American (AMR) AF: 0.412 AC: 17449 AN: 42326

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 8288 AN: 25832

East Asian (EAS) AF: 0.156 AC: 6133 AN: 39342

South Asian (SAS) AF: 0.235 AC: 20089 AN: 85486

European-Finnish (FIN) AF: 0.317 AC: 15623 AN: 49276

Middle Eastern (MID) AF: 0.383 AC: 1687 AN: 4410

European-Non Finnish (NFE) AF: 0.311 AC: 344153 AN: 1106350

Other (OTH) AF: 0.304 AC: 18146 AN: 59616

GnomAD4 genome AF: 0.323 AC: 49094 AN: 151866 Hom.: 8009 Cov.: 34 AF XY: 0.322 AC XY: 23932 AN XY: 74246

African (AFR) AF: 0.357 AC: 14713 AN: 41258

American (AMR) AF: 0.371 AC: 5677 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1123 AN: 3472

East Asian (EAS) AF: 0.141 AC: 726 AN: 5158

South Asian (SAS) AF: 0.228 AC: 1101 AN: 4826

European-Finnish (FIN) AF: 0.337 AC: 3574 AN: 10596

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.309 AC: 21000 AN: 67952

Other (OTH) AF: 0.335 AC: 707 AN: 2108

Alfa AF: 0.320 Hom.: 1411

Bravo AF: 0.331

Asia WGS AF: 0.193 AC: 671 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Left-right axis malformations (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.066
DANN	Benign	0.67
PhyloP100		-1.7
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: rs74578461; hg19: chr1-226127443; COSMIC: COSV64746410; COSMIC: COSV64746410;