21-28932594-A-T

Variant names:

• chr21-28932594-A-T
• rs2084219837
• NM_015565.3:c.4946T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015565.3(LTN1):​c.4946T>A​(p.Ile1649Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1649R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LTN1 NM_015565.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.87
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015565.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTN1	NM_015565.3	MANE Select	c.4946T>A	p.Ile1649Lys	missense	Exon 28 of 30	NP_056380.3	O94822-1
	LTN1	NM_001320766.2		c.4904T>A	p.Ile1635Lys	missense	Exon 27 of 29	NP_001307695.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTN1	ENST00000361371.10	TSL:1 MANE Select	c.4946T>A	p.Ile1649Lys	missense	Exon 28 of 30	ENSP00000354977.4	O94822-1
	LTN1	ENST00000614971.4	TSL:1	c.5084T>A	p.Ile1695Lys	missense	Exon 28 of 30	ENSP00000478783.1	O94822-3
	LTN1	ENST00000389194.7	TSL:1	c.4946T>A	p.Ile1649Lys	missense	Exon 28 of 30	ENSP00000373846.3	O94822-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		8.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.66		Gain of ubiquitination at I1649 (P = 0.0192)
MVP		0.24
MPC		0.85
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.59
gMVP		0.69
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs2084219837; hg19: chr21-30304916;