rs2084314912

Variant names:

• chr21-28943721-A-G
• rs2084314912
• NM_015565.3:c.4166T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015565.3(LTN1):​c.4166T>C​(p.Leu1389Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LTN1 NM_015565.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.75

Genes affected

LTN1 (HGNC:13082): (listerin E3 ubiquitin protein ligase 1) Like most RING finger proteins, LTN1 functions as an E3 ubiquitin ligase (Chu et al., 2009 [PubMed 19196968]).[supplied by OMIM, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTN1	NM_015565.3	c.4166T>C	p.Leu1389Ser	missense_variant	Exon 23 of 30	ENST00000361371.10	NP_056380.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTN1	ENST00000361371.10	c.4166T>C	p.Leu1389Ser	missense_variant	Exon 23 of 30	1	NM_015565.3	ENSP00000354977.4
LTN1	ENST00000614971.4	c.4304T>C	p.Leu1435Ser	missense_variant	Exon 23 of 30	1		ENSP00000478783.1
LTN1	ENST00000389194.7	c.4166T>C	p.Leu1389Ser	missense_variant	Exon 23 of 30	1		ENSP00000373846.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4304T>C (p.L1435S) alteration is located in exon 23 (coding exon 23) of the LTN1 gene. This alteration results from a T to C substitution at nucleotide position 4304, causing the leucine (L) at amino acid position 1435 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	N;N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.88
MutPred		0.67		Loss of helix (P = 0.0104);.;.;
MVP		0.38
MPC		1.0
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.74

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: rs2084314912; hg19: chr21-30316043;