21-28944401-T-G

Variant names:

• chr21-28944401-T-G
• rs1382835443
• NM_015565.3:c.3964A>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_015565.3(LTN1):​c.3964A>C​(p.Ile1322Leu) 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 Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LTN1 NM_015565.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.71

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03556201).
• BP6: Variant 21-28944401-T-G is Benign according to our data. Variant chr21-28944401-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3292292.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTN1	NM_015565.3	c.3964A>C	p.Ile1322Leu	missense_variant	Exon 22 of 30	ENST00000361371.10	NP_056380.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTN1	ENST00000361371.10	c.3964A>C	p.Ile1322Leu	missense_variant	Exon 22 of 30	1	NM_015565.3	ENSP00000354977.4
LTN1	ENST00000614971.4	c.4102A>C	p.Ile1368Leu	missense_variant	Exon 22 of 30	1		ENSP00000478783.1
LTN1	ENST00000389194.7	c.3964A>C	p.Ile1322Leu	missense_variant	Exon 22 of 30	1		ENSP00000373846.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 30, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.073	T;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.72	T;.;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.3	N;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.69	N;N;.
REVEL	Benign	0.040
Sift	Benign	1.0	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.16
MutPred		0.36		Loss of sheet (P = 0.0104);.;.;
MVP		0.043
MPC		0.24
ClinPred		0.35	T
GERP RS		4.2
Varity_R		0.046
gMVP		0.30

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: rs1382835443; hg19: chr21-30316723;