1-62206854-G-A

Variant names:

• chr1-62206854-G-A
• rs368156819
• NM_019079.5:c.226G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019079.5(L1TD1):​c.226G>A​(p.Asp76Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: L1TD1 NM_019079.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.345

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.203053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1TD1	NM_019079.5	c.226G>A	p.Asp76Asn	missense_variant	Exon 3 of 4	ENST00000498273.2	NP_061952.3
L1TD1	NM_001164835.2	c.226G>A	p.Asp76Asn	missense_variant	Exon 4 of 5		NP_001158307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1TD1	ENST00000498273.2	c.226G>A	p.Asp76Asn	missense_variant	Exon 3 of 4	1	NM_019079.5	ENSP00000419901.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460406 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726486

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.226G>A (p.D76N) alteration is located in exon 4 (coding exon 1) of the L1TD1 gene. This alteration results from a G to A substitution at nucleotide position 226, causing the aspartic acid (D) at amino acid position 76 to be replaced by an asparagine (N). 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	0.38
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.033
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.052	T
Polyphen		1.0	D
Vest4		0.18
MVP		0.44
MPC		0.041
ClinPred		0.42	T
GERP RS		2.2
Varity_R		0.063
gMVP		0.16

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: rs368156819; hg19: chr1-62672526;