1-156137757-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM5BP4

The NM_005572.4(LMNA):c.1712G>C(p.Arg571Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,546,932 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R571S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

LMNA
NM_005572.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.44

Publications

5 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

LMNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_005572.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-156137756-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14485.

BP4

Computational evidence support a benign effect (MetaRNN=0.33856887).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005572.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LMNA	NM_005572.4	MANE Plus Clinical	c.1712G>C	p.Arg571Pro	missense	Exon 10 of 10	NP_005563.1
LMNA	NM_170707.4	MANE Select	c.1698+14G>C		intron	N/A	NP_733821.1
LMNA	NM_001282625.2		c.1712G>C	p.Arg571Pro	missense	Exon 13 of 13	NP_001269554.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LMNA	ENST00000677389.1	MANE Plus Clinical	c.1712G>C	p.Arg571Pro	missense	Exon 10 of 10	ENSP00000503633.1
LMNA	ENST00000368300.9	TSL:1 MANE Select	c.1698+14G>C		intron	N/A	ENSP00000357283.4
LMNA	ENST00000368299.7	TSL:1	c.1698+14G>C		intron	N/A	ENSP00000357282.3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000404

AC:

AN:

148424

AF XY:

0.0000252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1394750

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

688032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31546

American (AMR)

AF:

0.000140

AC:

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.00

AC:

AN:

35870

South Asian (SAS)

AF:

0.00

AC:

AN:

79152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4264

European-Non Finnish (NFE)

AF:

0.0000269

AC:

AN:

1078914

Other (OTH)

AF:

0.000156

AC:

AN:

57828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000171

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

0.012

Eigen_PC

Benign

0.083

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.53

PhyloP100

1.4

PROVEAN

Benign

1.8

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

Sift4G

Benign

0.26

Polyphen

0.90

Vest4

0.44

MutPred

0.28

Loss of solvent accessibility (P = 0.0364)

MVP

0.81

ClinPred

0.12

GERP RS

4.7

Mutation Taster

=45/55

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over