Genetic Variant LMNTD2:p.Met193Ile (chr11-557617-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_173573.3(LMNTD2):c.579G>A(p.Met193Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,613,194 control chromosomes in the GnomAD database, including 1,311 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.037 ( 108 hom., cov: 33)

Exomes 𝑓: 0.038 ( 1203 hom. )

Consequence

LMNTD2
NM_173573.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.459

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018461645).

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNTD2	NM_173573.3 link	c.579G>A	p.Met193Ile	missense_variant	Exon 6 of 14	ENST00000329451.8	NP_775844.2	Q8IXW0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LMNTD2	ENST00000329451.8 link	c.579G>A	p.Met193Ile	missense_variant	Exon 6 of 14	1	NM_173573.3	ENSP00000331167.3	Q8IXW0
LMNTD2	ENST00000441853.5 link	c.600G>A	p.Met200Ile	missense_variant	Exon 7 of 9	3		ENSP00000393529.1	C9JV74
LMNTD2	ENST00000486629.1 link	c.609G>A	p.Met203Ile	missense_variant	Exon 6 of 7	5		ENSP00000435529.1	E9PJR3
LMNTD2-AS1	ENST00000527620.5 link	n.23C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0369

AC:

5617

AN:

152170

Hom.:

108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0302

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0329

Gnomad ASJ

AF:

0.0521

Gnomad EAS

AF:

0.00597

Gnomad SAS

AF:

0.0300

Gnomad FIN

AF:

0.0624

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0397

Gnomad OTH

AF:

0.0388

GnomAD3 exomes

AF:

0.0371

AC:

9293

AN:

250348

Hom.:

223

AF XY:

0.0381

AC XY:

5170

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.0289

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0509

Gnomad EAS exome

AF:

0.00604

Gnomad SAS exome

AF:

0.0369

Gnomad FIN exome

AF:

0.0622

Gnomad NFE exome

AF:

0.0407

Gnomad OTH exome

AF:

0.0467

GnomAD4 exome

AF:

0.0383

AC:

56003

AN:

1460906

Hom.:

1203

Cov.:

AF XY:

0.0386

AC XY:

28047

AN XY:

726728

show subpopulations

Gnomad4 AFR exome

AF:

0.0300

Gnomad4 AMR exome

AF:

0.0264

Gnomad4 ASJ exome

AF:

0.0534

Gnomad4 EAS exome

AF:

0.00539

Gnomad4 SAS exome

AF:

0.0367

Gnomad4 FIN exome

AF:

0.0643

Gnomad4 NFE exome

AF:

0.0383

Gnomad4 OTH exome

AF:

0.0420

GnomAD4 genome

AF:

0.0369

AC:

5625

AN:

152288

Hom.:

108

Cov.:

AF XY:

0.0379

AC XY:

2825

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0302

Gnomad4 AMR

AF:

0.0329

Gnomad4 ASJ

AF:

0.0521

Gnomad4 EAS

AF:

0.00598

Gnomad4 SAS

AF:

0.0298

Gnomad4 FIN

AF:

0.0624

Gnomad4 NFE

AF:

0.0397

Gnomad4 OTH

AF:

0.0393

Alfa

AF:

0.0307

Hom.:

Bravo

AF:

0.0353

TwinsUK

AF:

0.0399

AC:

148

ALSPAC

AF:

0.0355

AC:

137

ESP6500AA

AF:

0.0284

AC:

125

ESP6500EA

AF:

0.0408

AC:

351

ExAC

AF:

0.0374

AC:

4535

EpiCase

AF:

0.0463

EpiControl

AF:

0.0446

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.043

T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.61

T;T;T

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-1.1

PROVEAN

Benign

-1.7

N;D;D

REVEL

Benign

0.016

Sift

Benign

0.041

D;D;T

Sift4G

Benign

0.34

T;T;.

Polyphen

0.012

B;.;.

Vest4

0.079

MutPred

0.26

Gain of catalytic residue at L198 (P = 0.0212);.;.;

MPC

0.074

ClinPred

0.00095

GERP RS

0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.048

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over