Genetic Variant L1TD1:p.Pro410Ala (chr1-62210002-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_019079.5(L1TD1):c.1228C>G(p.Pro410Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000736 in 135,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. P410S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000074 ( 0 hom., cov: 31)

Consequence

L1TD1
NM_019079.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.24

Publications

4 publications found

Variant links:

Genes affected

L1TD1 (HGNC:25595): (LINE1 type transposase domain containing 1) Predicted to enable single-stranded RNA binding activity. Predicted to be involved in transposition, RNA-mediated. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

L1TD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036184847).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019079.5. 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
	L1TD1	NM_019079.5	MANE Select	c.1228C>G	p.Pro410Ala	missense	Exon 4 of 4	NP_061952.3
	L1TD1	NM_001164835.2		c.1228C>G	p.Pro410Ala	missense	Exon 5 of 5	NP_001158307.1	Q5T7N2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
L1TD1	ENST00000498273.2	TSL:1 MANE Select	c.1228C>G	p.Pro410Ala	missense	Exon 4 of 4	ENSP00000419901.1	Q5T7N2
L1TD1	ENST00000928897.1		c.1228C>G	p.Pro410Ala	missense	Exon 5 of 5	ENSP00000598956.1
L1TD1	ENST00000928898.1		c.1228C>G	p.Pro410Ala	missense	Exon 4 of 4	ENSP00000598957.1

Frequencies

GnomAD3 genomes

AF:

0.00000736

AC:

AN:

135884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000283

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000736

AC:

AN:

135884

Hom.:

Cov.:

AF XY:

0.0000150

AC XY:

AN XY:

66468

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000283

AC:

AN:

35384

American (AMR)

AF:

0.00

AC:

AN:

14028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3230

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61360

Other (OTH)

AF:

0.00

AC:

AN:

1856

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.010

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.021

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.00030

LIST_S2

Benign

0.33

M_CAP

Benign

0.0049

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.55

PhyloP100

-1.2

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.010

REVEL

Benign

0.0070

Sift

Benign

0.042

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.061

MutPred

0.19

Loss of glycosylation at P410 (P = 0.1393)

MVP

0.067

MPC

0.041

ClinPred

0.11

GERP RS

-2.0

Varity_R

0.025

gMVP

0.0095

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over