21-28932594-A-G

Variant names:

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

Variant summary

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

The NM_015565.3(LTN1):​c.4946T>C​(p.Ile1649Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• 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>C	p.Ile1649Thr	missense	Exon 28 of 30	NP_056380.3	O94822-1
	LTN1	NM_001320766.2		c.4904T>C	p.Ile1635Thr	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>C	p.Ile1649Thr	missense	Exon 28 of 30	ENSP00000354977.4	O94822-1
	LTN1	ENST00000614971.4	TSL:1	c.5084T>C	p.Ile1695Thr	missense	Exon 28 of 30	ENSP00000478783.1	O94822-3
	LTN1	ENST00000389194.7	TSL:1	c.4946T>C	p.Ile1649Thr	missense	Exon 28 of 30	ENSP00000373846.3	O94822-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461328 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727018

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111538

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	0.0093	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	N
PhyloP100		8.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.96	D
Vest4		0.72
MutPred		0.51		Loss of stability (P = 0.0137)
MVP		0.13
MPC		0.43
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.30
gMVP		0.40
Mutation Taster		=58/42	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;