1-156137743-C-T

Variant names:

• chr1-156137743-C-T
• rs4641
• NM_170707.4:c.1698C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_170707.4(LMNA):​c.1698C>T​(p.His566His) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,549,008 control chromosomes in the GnomAD database, including 53,510 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4005 hom., cov: 33)
  • Exomes 𝑓: 0.26 (49505 hom.)
• Consequence: LMNA NM_170707.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:31 O:1
• Conservation: PhyloP100: -1.60
• Publications: 95 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-156137743-C-T is Benign according to our data. Variant chr1-156137743-C-T is described in ClinVar as Benign. ClinVar VariationId is 48048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

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.1698C>T	p.His566His	splice_region synonymous	Exon 10 of 12	NP_733821.1	P02545-1
	LMNA	NM_005572.4	MANE Plus Clinical	c.1698C>T	p.His566His	synonymous	Exon 10 of 10	NP_005563.1	P02545-2
	LMNA	NM_001406985.1		c.1698C>T	p.His566His	splice_region synonymous	Exon 10 of 13	NP_001393914.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	ENST00000368300.9	TSL:1 MANE Select	c.1698C>T	p.His566His	splice_region synonymous	Exon 10 of 12	ENSP00000357283.4	P02545-1
	LMNA	ENST00000677389.1	MANE Plus Clinical	c.1698C>T	p.His566His	synonymous	Exon 10 of 10	ENSP00000503633.1	P02545-2
	LMNA	ENST00000368299.7	TSL:1	c.1698C>T	p.His566His	splice_region synonymous	Exon 10 of 12	ENSP00000357282.3	P02545-6

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32355 AN: 152082 Hom.: 4003 Cov.: 33

Gnomad AFR AF: 0.0934

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.221

GnomAD2 exomes AF: 0.263 AC: 40459 AN: 153988 AF XY: 0.266

Gnomad AFR exome AF: 0.0906

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.265

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.263 AC: 367534 AN: 1396808 Hom.: 49505 Cov.: 34 AF XY: 0.264 AC XY: 182035 AN XY: 689016

African (AFR) AF: 0.0862 AC: 2722 AN: 31594

American (AMR) AF: 0.317 AC: 11328 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 7395 AN: 25180

East Asian (EAS) AF: 0.243 AC: 8705 AN: 35892

South Asian (SAS) AF: 0.294 AC: 23239 AN: 79160

European-Finnish (FIN) AF: 0.179 AC: 8584 AN: 48074

Middle Eastern (MID) AF: 0.260 AC: 1145 AN: 4396

European-Non Finnish (NFE) AF: 0.268 AC: 289299 AN: 1078952

Other (OTH) AF: 0.261 AC: 15117 AN: 57858

GnomAD4 genome AF: 0.213 AC: 32371 AN: 152200 Hom.: 4005 Cov.: 33 AF XY: 0.213 AC XY: 15815 AN XY: 74396

African (AFR) AF: 0.0932 AC: 3869 AN: 41530

American (AMR) AF: 0.283 AC: 4324 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 987 AN: 3472

East Asian (EAS) AF: 0.252 AC: 1304 AN: 5172

South Asian (SAS) AF: 0.305 AC: 1474 AN: 4828

European-Finnish (FIN) AF: 0.170 AC: 1802 AN: 10612

Middle Eastern (MID) AF: 0.253 AC: 74 AN: 292

European-Non Finnish (NFE) AF: 0.261 AC: 17752 AN: 67982

Other (OTH) AF: 0.223 AC: 471 AN: 2114

Alfa AF: 0.247 Hom.: 12593

Bravo AF: 0.216

Asia WGS AF: 0.273 AC: 949 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	3	not provided (4)
-	-	2	Mandibuloacral dysplasia with type A lipodystrophy (2)
-	-	1	Cardiomyopathy (1)
-	-	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 (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	-0.50
CADD	Benign	8.6
DANN	Benign	0.88
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs4641; hg19: chr1-156107534; COSMIC: COSV61541921; COSMIC: COSV61541921;