dbSNP rs80356813: LMNA:p.Leu587Leu (chr1-156138550-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_170707.4(LMNA):c.1761G>A(p.Leu587Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,612,680 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L587L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 4 hom. )

Consequence

LMNA
NM_170707.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: 1.18

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: Ambry Genetics, Orphanet, G2P
familial partial lipodystrophy, Dunnigan type
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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, G2P, Labcorp Genetics (formerly Invitae)
Hutchinson-Gilford progeria syndrome
Inheritance: SD, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
lipodystrophy
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
atrioventricular block
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Charcot-Marie-Tooth disease type 2B1
Inheritance: AD, AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
heart-hand syndrome, Slovenian type
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Ambry Genetics, 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 1-156138550-G-A is Benign according to our data. Variant chr1-156138550-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.18 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00196 (298/152378) while in subpopulation NFE AF = 0.00322 (219/68038). AF 95% confidence interval is 0.00287. There are 2 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170707.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LMNA	NM_170707.4	MANE Select	c.1761G>A	p.Leu587Leu	synonymous	Exon 11 of 12	NP_733821.1	P02545-1
LMNA	NM_001406985.1		c.1761G>A	p.Leu587Leu	synonymous	Exon 11 of 13	NP_001393914.1
LMNA	NM_001406983.1		c.1761G>A	p.Leu587Leu	synonymous	Exon 13 of 14	NP_001393912.1	A0A384MQX1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LMNA	ENST00000368300.9	TSL:1 MANE Select	c.1761G>A	p.Leu587Leu	synonymous	Exon 11 of 12	ENSP00000357283.4	P02545-1
LMNA	ENST00000368299.7	TSL:1	c.1761G>A	p.Leu587Leu	synonymous	Exon 11 of 12	ENSP00000357282.3	P02545-6
LMNA	ENST00000675667.1		c.1761G>A	p.Leu587Leu	synonymous	Exon 12 of 12	ENSP00000501803.1	A0A6Q8PFJ0

Frequencies

GnomAD3 genomes

AF:

0.00196

AC:

298

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00190

AC:

463

AN:

244258

AF XY:

0.00188

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.000707

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00692

Gnomad NFE exome

AF:

0.00273

Gnomad OTH exome

AF:

0.00150

GnomAD4 exome

AF:

0.00188

AC:

2744

AN:

1460302

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

1360

AN XY:

726476

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33466

American (AMR)

AF:

0.0000672

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.000920

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00635

AC:

333

AN:

52410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00206

AC:

2286

AN:

1111768

Other (OTH)

AF:

0.00148

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

170

340

509

679

849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00196

AC:

298

AN:

152378

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

153

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41590

American (AMR)

AF:

0.000523

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00546

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00322

AC:

219

AN:

68038

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00220

Hom.:

Bravo

AF:

0.00119

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00202

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

not provided (6)

Cardiomyopathy (3)

Cardiovascular phenotype (1)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 2 (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism

(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