rs520973

Variant names:

• chr1-156138228-C-T
• rs520973
• NM_170707.4:c.1699-260C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_170707.4(LMNA):​c.1699-260C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 586,598 control chromosomes in the GnomAD database, including 6,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4141 hom., cov: 32)
  • Exomes 𝑓: 0.088 (2684 hom.)
• Consequence: LMNA NM_170707.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.47
• Publications: 2 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-156138228-C-T is Benign according to our data. Variant chr1-156138228-C-T is described in ClinVar as Benign. ClinVar VariationId is 683615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	NM_170707.4	MANE Select	c.1699-260C>T		intron	N/A	NP_733821.1
	LMNA	NM_001406985.1		c.1699-260C>T		intron	N/A	NP_001393914.1
	LMNA	NM_001406983.1		c.1699-260C>T		intron	N/A	NP_001393912.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	ENST00000368300.9	TSL:1 MANE Select	c.1699-260C>T		intron	N/A	ENSP00000357283.4
	LMNA	ENST00000368299.7	TSL:1	c.1699-260C>T		intron	N/A	ENSP00000357282.3
	LMNA	ENST00000496738.6	TSL:2	n.2642C>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25965 AN: 152086 Hom.: 4130 Cov.: 32

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0910

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0225

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.0704

Gnomad OTH AF: 0.137

GnomAD4 exome AF: 0.0877 AC: 38116 AN: 434394 Hom.: 2684 Cov.: 4 AF XY: 0.0903 AC XY: 20566 AN XY: 227840

African (AFR) AF: 0.429 AC: 5231 AN: 12202

American (AMR) AF: 0.0779 AC: 1416 AN: 18168

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 1739 AN: 13462

East Asian (EAS) AF: 0.0154 AC: 466 AN: 30204

South Asian (SAS) AF: 0.140 AC: 6047 AN: 43078

European-Finnish (FIN) AF: 0.0538 AC: 1531 AN: 28476

Middle Eastern (MID) AF: 0.165 AC: 316 AN: 1918

European-Non Finnish (NFE) AF: 0.0715 AC: 18712 AN: 261536

Other (OTH) AF: 0.105 AC: 2658 AN: 25350

GnomAD4 genome AF: 0.171 AC: 26006 AN: 152204 Hom.: 4141 Cov.: 32 AF XY: 0.168 AC XY: 12478 AN XY: 74422

African (AFR) AF: 0.425 AC: 17626 AN: 41490

American (AMR) AF: 0.0908 AC: 1389 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 456 AN: 3470

East Asian (EAS) AF: 0.0224 AC: 116 AN: 5178

South Asian (SAS) AF: 0.127 AC: 615 AN: 4828

European-Finnish (FIN) AF: 0.0564 AC: 598 AN: 10612

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.0703 AC: 4784 AN: 68008

Other (OTH) AF: 0.136 AC: 287 AN: 2116

Alfa AF: 0.163 Hom.: 688

Bravo AF: 0.183

Asia WGS AF: 0.0970 AC: 336 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.12
DANN	Benign	0.31
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs520973; hg19: chr1-156108019;