rs41313880

Variant names:

• chr1-156130617-C-T
• rs41313880
• NM_170707.4:c.357C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_170707.4(LMNA):​c.357C>T​(p.Arg119Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,613,826 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (12 hom.)
• Consequence: LMNA NM_170707.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.01863
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:34 O:1
• Conservation: PhyloP100: 0.736
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 1-156130617-C-T is Benign according to our data. Variant chr1-156130617-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48062.
• BP7: Synonymous conserved (PhyloP=0.736 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0031 (472/152352) while in subpopulation NFE AF = 0.00353 (240/68038). AF 95% confidence interval is 0.00316. There are 2 homozygotes in GnomAd4. There are 251 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	NM_170707.4	MANE Select	c.357C>T	p.Arg119Arg	splice_region synonymous	Exon 2 of 12	NP_733821.1	P02545-1
	LMNA	NM_005572.4	MANE Plus Clinical	c.357C>T	p.Arg119Arg	splice_region synonymous	Exon 2 of 10	NP_005563.1	P02545-2
	LMNA	NM_001406993.1		c.-202C>T		splice_region	Exon 2 of 12	NP_001393922.1	H0YAB0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	ENST00000368300.9	TSL:1 MANE Select	c.357C>T	p.Arg119Arg	splice_region synonymous	Exon 2 of 12	ENSP00000357283.4	P02545-1
	LMNA	ENST00000677389.1	MANE Plus Clinical	c.357C>T	p.Arg119Arg	splice_region synonymous	Exon 2 of 10	ENSP00000503633.1	P02545-2
	LMNA	ENST00000368299.7	TSL:1	c.357C>T	p.Arg119Arg	splice_region synonymous	Exon 2 of 12	ENSP00000357282.3	P02545-6

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152234 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00312 AC: 784 AN: 251304 AF XY: 0.00297

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00381

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00311 AC: 4549 AN: 1461474 Hom.: 12 Cov.: 31 AF XY: 0.00298 AC XY: 2170 AN XY: 727050

African (AFR) AF: 0.000418 AC: 14 AN: 33470

American (AMR) AF: 0.00132 AC: 59 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86240

European-Finnish (FIN) AF: 0.0120 AC: 643 AN: 53408

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5590

European-Non Finnish (NFE) AF: 0.00326 AC: 3623 AN: 1111842

Other (OTH) AF: 0.00263 AC: 159 AN: 60364

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152352 Hom.: 2 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74496

African (AFR) AF: 0.000337 AC: 14 AN: 41582

American (AMR) AF: 0.00314 AC: 48 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0145 AC: 154 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00353 AC: 240 AN: 68038

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00283 Hom.: 1

Bravo AF: 0.00227

EpiCase AF: 0.00267

EpiControl AF: 0.00249

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	7	not provided (8)
-	-	2	Cardiomyopathy (2)
-	-	2	Emery-Dreifuss muscular dystrophy (2)
-	-	2	Primary dilated cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Charcot-Marie-Tooth disease type 2B1 (1)
-	-	1	Congenital muscular dystrophy due to LMNA mutation (1)
-	1	-	Dilated cardiomyopathy 1A (1)
-	-	1	Emery-Dreifuss muscular dystrophy 2, autosomal dominant (1)
-	-	1	Familial partial lipodystrophy, Dunnigan type (1)
-	-	1	Hutchinson-Gilford syndrome (1)
-	-	1	Lethal tight skin contracture syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.86
PhyloP100		0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.019
dbscSNV1_RF	Benign	0.69
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

Other links and lift over

dbSNP: rs41313880; hg19: chr1-156100408;