21-28946231-C-A

Position:

• chr21-28946231-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015565.3(LTN1):​c.3544G>T​(p.Asp1182Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LTN1 NM_015565.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1457642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTN1	NM_015565.3	c.3544G>T	p.Asp1182Tyr	missense_variant	20/30	ENST00000361371.10	NP_056380.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTN1	ENST00000361371.10	c.3544G>T	p.Asp1182Tyr	missense_variant	20/30	1	NM_015565.3	ENSP00000354977.4
LTN1	ENST00000614971.4	c.3682G>T	p.Asp1228Tyr	missense_variant	20/30	1		ENSP00000478783.1
LTN1	ENST00000389194.7	c.3544G>T	p.Asp1182Tyr	missense_variant	20/30	1		ENSP00000373846.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.3682G>T (p.D1228Y) alteration is located in exon 20 (coding exon 20) of the LTN1 gene. This alteration results from a G to T substitution at nucleotide position 3682, causing the aspartic acid (D) at amino acid position 1228 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	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.53
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.014
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.74	T;.;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N;N;.
REVEL	Benign	0.052
Sift	Benign	0.97	T;T;.
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0030	B;.;.
Vest4		0.49
MutPred		0.32		Gain of helix (P = 0.027);.;.;
MVP		0.068
MPC		0.31
ClinPred		0.72	D
GERP RS		5.0
Varity_R		0.098
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-30318553;