chr1-156137208-G-A

Variant names:

• chr1-156137208-G-A
• rs80356812
• NM_170707.4:c.1584G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_170707.4(LMNA):​c.1584G>A​(p.Thr528Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,595,766 control chromosomes in the GnomAD database, including 2 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. T528T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: LMNA NM_170707.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -3.18
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-156137208-G-A is Benign according to our data. Variant chr1-156137208-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000236 (36/152310) while in subpopulation EAS AF = 0.00561 (29/5170). AF 95% confidence interval is 0.00401. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.1584G>A	p.Thr528Thr	synonymous	Exon 9 of 12	NP_733821.1
	LMNA	NM_005572.4	MANE Plus Clinical	c.1584G>A	p.Thr528Thr	synonymous	Exon 9 of 10	NP_005563.1
	LMNA	NM_001406985.1		c.1584G>A	p.Thr528Thr	synonymous	Exon 9 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.1584G>A	p.Thr528Thr	synonymous	Exon 9 of 12	ENSP00000357283.4
	LMNA	ENST00000677389.1	MANE Plus Clinical	c.1584G>A	p.Thr528Thr	synonymous	Exon 9 of 10	ENSP00000503633.1
	LMNA	ENST00000368299.7	TSL:1	c.1584G>A	p.Thr528Thr	synonymous	Exon 9 of 12	ENSP00000357282.3

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00560

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000512 AC: 110 AN: 214644 AF XY: 0.000429

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00667

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000418

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 160 AN: 1443456 Hom.: 2 Cov.: 32 AF XY: 0.000102 AC XY: 73 AN XY: 716944

African (AFR) AF: 0.00 AC: 0 AN: 33242

American (AMR) AF: 0.0000240 AC: 1 AN: 41664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25808

East Asian (EAS) AF: 0.00287 AC: 112 AN: 38968

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000362 AC: 40 AN: 1104478

Other (OTH) AF: 0.000100 AC: 6 AN: 59720

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74466

African (AFR) AF: 0.0000722 AC: 3 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.00561 AC: 29 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000584 Hom.: 0

Bravo AF: 0.000204

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Primary dilated cardiomyopathy (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	-0.72
CADD	Benign	3.6
DANN	Benign	0.87
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs80356812; hg19: chr1-156106999;