NM_170707.4:c.357-739T>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_170707.4(LMNA):c.357-739T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 769,892 control chromosomes in the GnomAD database, including 9,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 4791 hom., cov: 32)

Exomes 𝑓: 0.090 ( 4327 hom. )

Consequence

LMNA
NM_170707.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.34

Publications

11 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017819703).

BP6

Variant 1-156129878-T-G is Benign according to our data. Variant chr1-156129878-T-G is described in ClinVar as Benign. ClinVar VariationId is 192190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4 link	c.357-739T>G		intron_variant	Intron 1 of 11	ENST00000368300.9	NP_733821.1	P02545-1A0A384MQX1
LMNA	NM_005572.4 link	c.357-739T>G		intron_variant	Intron 1 of 9	ENST00000677389.1	NP_005563.1	P02545-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 link	c.357-739T>G		intron_variant	Intron 1 of 11	1	NM_170707.4	ENSP00000357283.4		P02545-1
LMNA	ENST00000677389.1 link	c.357-739T>G		intron_variant	Intron 1 of 9		NM_005572.4	ENSP00000503633.1		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.181

AC:

27542

AN:

151952

Hom.:

4757

Cov.:

show subpopulations

Gnomad AFR

AF:

0.461

Gnomad AMI

AF:

0.0846

Gnomad AMR

AF:

0.0943

Gnomad ASJ

AF:

0.132

Gnomad EAS

AF:

0.0229

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.0565

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.0711

Gnomad OTH

AF:

0.149

GnomAD2 exomes

AF:

0.100

AC:

22581

AN:

225092

AF XY:

0.100

show subpopulations

Gnomad AFR exome

AF:

0.480

Gnomad AMR exome

AF:

0.0650

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.0195

Gnomad FIN exome

AF:

0.0565

Gnomad NFE exome

AF:

0.0721

Gnomad OTH exome

AF:

0.0937

GnomAD4 exome

AF:

0.0904

AC:

55866

AN:

617822

Hom.:

4327

Cov.:

AF XY:

0.0928

AC XY:

31185

AN XY:

336006

show subpopulations

African (AFR)

AF:

0.466

AC:

8186

AN:

17552

American (AMR)

AF:

0.0685

AC:

2913

AN:

42522

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

2699

AN:

20744

East Asian (EAS)

AF:

0.0155

AC:

556

AN:

35906

South Asian (SAS)

AF:

0.142

AC:

9622

AN:

67684

European-Finnish (FIN)

AF:

0.0545

AC:

2812

AN:

51588

Middle Eastern (MID)

AF:

0.167

AC:

483

AN:

2900

European-Non Finnish (NFE)

AF:

0.0724

AC:

25077

AN:

346244

Other (OTH)

AF:

0.108

AC:

3518

AN:

32682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2296

4592

6889

9185

11481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

260

520

780

1040

1300

<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:

0.182

AC:

27624

AN:

152070

Hom.:

4791

Cov.:

AF XY:

0.179

AC XY:

13340

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.461

AC:

19112

AN:

41430

American (AMR)

AF:

0.0941

AC:

1438

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.132

AC:

459

AN:

3466

East Asian (EAS)

AF:

0.0228

AC:

118

AN:

5176

South Asian (SAS)

AF:

0.128

AC:

619

AN:

4818

European-Finnish (FIN)

AF:

0.0565

AC:

599

AN:

10594

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0711

AC:

4831

AN:

67986

Other (OTH)

AF:

0.149

AC:

314

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

928

1857

2785

3714

4642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.118

Hom.:

4703

Bravo

AF:

0.196

TwinsUK

AF:

0.0599

AC:

222

ALSPAC

AF:

0.0646

AC:

249

ESP6500AA

AF:

0.450

AC:

788

ESP6500EA

AF:

0.0721

AC:

287

ExAC

AF:

0.101

AC:

11773

Asia WGS

AF:

0.108

AC:

375

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hutchinson-Gilford syndrome

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.11

Eigen_PC

Benign

-0.0031

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0018

MetaSVM

Uncertain

0.27

PhyloP100

1.3

PROVEAN

Benign

-0.25

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Vest4

0.28

ClinPred

0.065

GERP RS

4.4

Mutation Taster

=95/5

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over