rs1057518971

chr1-156115048-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_170707.4(LMNA):c.130G>T(p.Val44Phe) 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 ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V44V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.21

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_170707.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LMNA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785
• PP5: Variant 1-156115048-G-T is Pathogenic according to our data. Variant chr1-156115048-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 374201.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr1-156115048-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.130G>T	p.Val44Phe	missense_variant	1/12	ENST00000368300.9
LMNA	NM_005572.4	c.130G>T	p.Val44Phe	missense_variant	1/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.130G>T	p.Val44Phe	missense_variant	1/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.130G>T	p.Val44Phe	missense_variant	1/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1443884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716570

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital muscular dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 28, 2013

- -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 11, 2020

This sequence change replaces valine with phenylalanine at codon 44 of the LMNA protein (p.Val44Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Emery-Dreifuss muscular dystrophy (Invitae). ClinVar contains an entry for this variant (Variation ID: 374201). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
CardioboostCm	Uncertain	0.19
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	29
Dann	Uncertain	0.99
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.0	M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Benign	0.60	T;T;T;T;T
Polyphen		0.74	P;.;P;P;.
Vest4		0.72
MutPred		0.58		Loss of disorder (P = 0.106);Loss of disorder (P = 0.106);Loss of disorder (P = 0.106);Loss of disorder (P = 0.106);Loss of disorder (P = 0.106);
MVP		0.93
MPC		2.3
ClinPred		0.98	D
GERP RS		2.8
Varity_R		0.54
gMVP		0.99

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: rs1057518971; hg19: chr1-156084839;