21-28932525-G-A

Variant names:

• chr21-28932525-G-A
• rs1418219001
• NM_015565.3:c.5015C>T

Variant summary

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

The NM_015565.3(LTN1):​c.5015C>T​(p.Ala1672Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LTN1 NM_015565.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.51

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.5015C>T	p.Ala1672Val	missense_variant	Exon 28 of 30	ENST00000361371.10	NP_056380.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTN1	ENST00000361371.10	c.5015C>T	p.Ala1672Val	missense_variant	Exon 28 of 30	1	NM_015565.3	ENSP00000354977.4
LTN1	ENST00000614971.4	c.5153C>T	p.Ala1718Val	missense_variant	Exon 28 of 30	1		ENSP00000478783.1
LTN1	ENST00000389194.7	c.5015C>T	p.Ala1672Val	missense_variant	Exon 28 of 30	1		ENSP00000373846.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5153C>T (p.A1718V) alteration is located in exon 28 (coding exon 28) of the LTN1 gene. This alteration results from a C to T substitution at nucleotide position 5153, causing the alanine (A) at amino acid position 1718 to be replaced by a valine (V). 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	Uncertain	0.51
BayesDel_addAF	Benign	0.0018	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.3	N;N;.
REVEL	Benign	0.26
Sift	Benign	0.054	T;T;.
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.79
MutPred		0.32		Gain of helix (P = 0.0696);.;.;
MVP		0.26
MPC		0.83
ClinPred		0.90	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.54

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: rs1418219001; hg19: chr21-30304847;