21-28941338-C-T

Variant names:

• chr21-28941338-C-T
• rs2084295833
• NM_015565.3:c.4364G>A

Variant summary

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

The NM_015565.3(LTN1):​c.4364G>A​(p.Cys1455Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,174 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: LTN1 NM_015565.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55

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.4364G>A	p.Cys1455Tyr	missense_variant	Exon 25 of 30	ENST00000361371.10	NP_056380.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTN1	ENST00000361371.10	c.4364G>A	p.Cys1455Tyr	missense_variant	Exon 25 of 30	1	NM_015565.3	ENSP00000354977.4
LTN1	ENST00000614971.4	c.4502G>A	p.Cys1501Tyr	missense_variant	Exon 25 of 30	1		ENSP00000478783.1
LTN1	ENST00000389194.7	c.4364G>A	p.Cys1455Tyr	missense_variant	Exon 25 of 30	1		ENSP00000373846.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461174 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726924

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000448

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4502G>A (p.C1501Y) alteration is located in exon 25 (coding exon 25) of the LTN1 gene. This alteration results from a G to A substitution at nucleotide position 4502, causing the cysteine (C) at amino acid position 1501 to be replaced by a tyrosine (Y). 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	0.11
BayesDel_addAF	Benign	-0.0069	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.82	T;.;T
M_CAP	Benign	0.0039	T
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Benign	0.16
Sift	Benign	0.20	T;T;.
Sift4G	Uncertain	0.049	D;D;D
Polyphen		0.95	P;.;.
Vest4		0.71
MutPred		0.57		Gain of sheet (P = 0.1945);.;.;
MVP		0.38
MPC		0.90
ClinPred		0.75	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.33

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: rs2084295833; hg19: chr21-30313660;