rs397517889

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_170707.4(LMNA):​c.1129C>A​(p.Arg377Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

LMNA
NM_170707.4 missense

Scores

16
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.87
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_170707.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-156136093-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the LMNA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 178 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 2.3673 (below the threshold of 3.09). Trascript score misZ: 3.0905 (above the threshold of 3.09). GenCC associations: The gene is linked to familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.951
PP5
Variant 1-156136093-C-A is Pathogenic according to our data. Variant chr1-156136093-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LMNANM_170707.4 linkc.1129C>A p.Arg377Ser missense_variant Exon 6 of 12 ENST00000368300.9 NP_733821.1 P02545-1A0A384MQX1
LMNANM_005572.4 linkc.1129C>A p.Arg377Ser missense_variant Exon 6 of 10 ENST00000677389.1 NP_005563.1 P02545-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LMNAENST00000368300.9 linkc.1129C>A p.Arg377Ser missense_variant Exon 6 of 12 1 NM_170707.4 ENSP00000357283.4 P02545-1
LMNAENST00000677389.1 linkc.1129C>A p.Arg377Ser missense_variant Exon 6 of 10 NM_005572.4 ENSP00000503633.1 P02545-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
.;.;.;D;.;.;.;.;D
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.81
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.1
H;.;H;H;H;.;.;.;.
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-5.9
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;D;D;.;.;D;.;.
Vest4
0.91
MutPred
0.78
Gain of phosphorylation at R377 (P = 0.0587);Gain of phosphorylation at R377 (P = 0.0587);Gain of phosphorylation at R377 (P = 0.0587);Gain of phosphorylation at R377 (P = 0.0587);Gain of phosphorylation at R377 (P = 0.0587);.;.;.;.;
MVP
0.99
MPC
2.2
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.8
Varity_R
0.99
gMVP
0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-156105884; API