NM_003240.5:c.*317C>G

Variant names:

• chr1-225937124-G-C
• rs114492272
• NM_003240.5:c.*317C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003240.5(LEFTY2):​c.*317C>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 0.00286 in 496,126 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: LEFTY2 NM_003240.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0380
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-225937124-G-C is Benign according to our data. Variant chr1-225937124-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 295963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00683 (1040/152264) while in subpopulation AFR AF = 0.0228 (947/41534). AF 95% confidence interval is 0.0216. There are 15 homozygotes in GnomAd4. There are 461 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1040 AD gene.

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.*317C>G		3_prime_UTR	Exon 4 of 4	NP_003231.2
	LEFTY2	NM_001172425.3		c.*317C>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.*317C>G		3_prime_UTR	Exon 4 of 4	ENSP00000355785.5	O00292-1
	LEFTY2	ENST00000420304.6	TSL:2	c.*317C>G		3_prime_UTR	Exon 5 of 5	ENSP00000388009.2	O00292-2
	ENSG00000248322	ENST00000513672.1	TSL:2	n.175+259C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00683 AC: 1039 AN: 152146 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.00110 AC: 379 AN: 343862 Hom.: 5 Cov.: 0 AF XY: 0.000895 AC XY: 163 AN XY: 182050

African (AFR) AF: 0.0216 AC: 218 AN: 10104

American (AMR) AF: 0.00285 AC: 43 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10518

East Asian (EAS) AF: 0.00 AC: 0 AN: 20644

South Asian (SAS) AF: 0.000187 AC: 8 AN: 42672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19172

Middle Eastern (MID) AF: 0.00678 AC: 10 AN: 1474

European-Non Finnish (NFE) AF: 0.000245 AC: 50 AN: 204432

Other (OTH) AF: 0.00253 AC: 50 AN: 19772

GnomAD4 genome AF: 0.00683 AC: 1040 AN: 152264 Hom.: 15 Cov.: 32 AF XY: 0.00619 AC XY: 461 AN XY: 74448

African (AFR) AF: 0.0228 AC: 947 AN: 41534

American (AMR) AF: 0.00399 AC: 61 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68018

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00175 Hom.: 1

Bravo AF: 0.00813

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.9
DANN	Benign	0.52
PhyloP100		-0.038
Mutation Taster		=100/0	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: rs114492272; hg19: chr1-226124824;