1-225886991-C-A

Position:

• chr1-225886991-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_020997.4(LEFTY1):​c.837G>T​(p.Glu279Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E279K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LEFTY1 NM_020997.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.55

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12960353).
• BP6: Variant 1-225886991-C-A is Benign according to our data. Variant chr1-225886991-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3290432.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEFTY1	NM_020997.4	c.837G>T	p.Glu279Asp	missense_variant	4/4	ENST00000272134.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEFTY1	ENST00000272134.5	c.837G>T	p.Glu279Asp	missense_variant	4/4	1	NM_020997.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457684 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 724518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	L
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.12
Sift	Benign	0.23	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.061
MutPred		0.55		Gain of sheet (P = 0.1451);
MVP		0.55
MPC		0.11
ClinPred		0.60	D
GERP RS		0.74
Varity_R		0.11
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs1046194729; hg19: chr1-226074691; COSMIC: COSV105843820; COSMIC: COSV105843820;