GeneBe

rs797044488

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_170707.4(LMNA):​c.1968+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

LMNA
NM_170707.4 splice_region, intron

Scores

2
Splicing: ADA: 0.9997
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 8.11

Publications

10 publications found
Variant links:
Genes affected
LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]
LMNA Gene-Disease associations (from GenCC):
  • dilated cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • dilated cardiomyopathy 1A
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
  • familial partial lipodystrophy, Dunnigan type
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
  • Hutchinson-Gilford progeria syndrome
    Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • restrictive dermopathy 2
    Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
  • Emery-Dreifuss muscular dystrophy 2, autosomal dominant
    Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
  • atrioventricular block
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • heart-hand syndrome, Slovenian type
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
  • Charcot-Marie-Tooth disease type 2B1
    Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
  • Emery-Dreifuss muscular dystrophy 3, autosomal recessive
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • mandibuloacral dysplasia with type A lipodystrophy
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
  • atrial fibrillation
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • atypical Werner syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal dominant Emery-Dreifuss muscular dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital muscular dystrophy due to LMNA mutation
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • lethal restrictive dermopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • LMNA-related cardiocutaneous progeria syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal recessive Emery-Dreifuss muscular dystrophy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal semi-dominant severe lipodystrophic laminopathy
    Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
  • arrhythmogenic right ventricular cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
Variant 1-156138762-G-A is Pathogenic according to our data. Variant chr1-156138762-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LMNANM_170707.4 linkc.1968+5G>A splice_region_variant, intron_variant Intron 11 of 11 ENST00000368300.9 NP_733821.1 P02545-1A0A384MQX1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LMNAENST00000368300.9 linkc.1968+5G>A splice_region_variant, intron_variant Intron 11 of 11 1 NM_170707.4 ENSP00000357283.4 P02545-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hutchinson-Gilford syndrome Pathogenic:2Other:1
May 16, 2023
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PS4, PM2, PP3, PP5 -

-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Dec 11, 2023
3billion
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Intron variant: previously reported to result in an inframe deletion from an in vitro assay and reduce expression level of the gene (PMID: 22065502). Intron variant: previously reported to result in an inframe deletion from an in vitro assay and reduce expression level of the gene (PMID: 22065502). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Hutchinson-Gilford progeria syndrome, atypical Pathogenic:1
Aug 01, 2015
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.35
CADD
Benign
23
DANN
Benign
0.97
PhyloP100
8.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs797044488; hg19: chr1-156108553; API