Genetic Variant LMNTD2:p.Ile75Asn (chr11-558701-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173573.3(LMNTD2):c.224T>A(p.Ile75Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 1,454,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

LMNTD2
NM_173573.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.665

Variant links:

Genes affected

LMNTD2 (HGNC:28561): (lamin tail domain containing 2) Predicted to be a structural constituent of chromatin. Predicted to be involved in regulation of chromatin assembly. Predicted to act upstream of or within positive regulation of mRNA splicing, via spliceosome. Predicted to be active in lamin filament. [provided by Alliance of Genome Resources, Apr 2022]

LMNTD2 links:

LMNTD2-AS1 (HGNC:41204): (LMNTD2 antisense RNA 1)

LMNTD2-AS1 links:

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ACMG classification

Classification made for transcript

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=0.24625778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNTD2	NM_173573.3 link	c.224T>A	p.Ile75Asn	missense_variant	Exon 3 of 14	ENST00000329451.8	NP_775844.2	Q8IXW0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNTD2	ENST00000329451.8 link	c.224T>A	p.Ile75Asn	missense_variant	Exon 3 of 14	1	NM_173573.3	ENSP00000331167.3		Q8IXW0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000849

AC:

AN:

235474

Hom.:

AF XY:

0.00000780

AC XY:

AN XY:

128272

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000190

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000894

AC:

AN:

1454070

Hom.:

Cov.:

AF XY:

0.00000830

AC XY:

AN XY:

722910

show subpopulations

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:

0.0000193

Gnomad4 NFE exome

AF:

0.00000901

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000624

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.224T>A (p.I75N) alteration is located in exon 3 (coding exon 3) of the LMNTD2 gene. This alteration results from a T to A substitution at nucleotide position 224, causing the isoleucine (I) at amino acid position 75 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

Pathogenic

0.79

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.84

T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.76

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Benign

0.21

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.85

MutPred

0.24

Gain of disorder (P = 0.0299);.;.;

MVP

0.55

MPC

0.52

ClinPred

0.98

GERP RS

4.0

Varity_R

0.73

gMVP

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over