chr1-156139185-G-C

Variant names:

• chr1-156139185-G-C
• rs7339
• NM_170707.4:c.*79G>C

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.*79G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0889 in 1,608,040 control chromosomes in the GnomAD database, including 11,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4059 hom., cov: 31)
  • Exomes 𝑓: 0.080 (7584 hom.)
• Consequence: LMNA NM_170707.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.0620
• 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: 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=-0.9).
• BP6: Variant 1-156139185-G-C is Benign according to our data. Variant chr1-156139185-G-C is described in ClinVar as Benign. ClinVar VariationId is 66756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.416 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.*79G>C		3_prime_UTR	Exon 12 of 12	NP_733821.1
	LMNA	NM_001406983.1		c.*79G>C		3_prime_UTR	Exon 14 of 14	NP_001393912.1
	LMNA	NM_001406991.1		c.*79G>C		3_prime_UTR	Exon 13 of 13	NP_001393920.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	ENST00000368300.9	TSL:1 MANE Select	c.*79G>C		3_prime_UTR	Exon 12 of 12	ENSP00000357283.4
	LMNA	ENST00000368299.7	TSL:1	c.*79G>C		3_prime_UTR	Exon 12 of 12	ENSP00000357282.3
	LMNA	ENST00000675667.1		c.*206G>C		3_prime_UTR	Exon 12 of 12	ENSP00000501803.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25736 AN: 151688 Hom.: 4048 Cov.: 31

Gnomad AFR AF: 0.421

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.0905

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0567

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.0704

Gnomad OTH AF: 0.135

GnomAD4 exome AF: 0.0804 AC: 117154 AN: 1456234 Hom.: 7584 Cov.: 34 AF XY: 0.0825 AC XY: 59754 AN XY: 724244

African (AFR) AF: 0.439 AC: 14667 AN: 33388

American (AMR) AF: 0.0666 AC: 2946 AN: 44212

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3398 AN: 25956

East Asian (EAS) AF: 0.0159 AC: 632 AN: 39654

South Asian (SAS) AF: 0.140 AC: 12076 AN: 85976

European-Finnish (FIN) AF: 0.0539 AC: 2727 AN: 50624

Middle Eastern (MID) AF: 0.154 AC: 879 AN: 5710

European-Non Finnish (NFE) AF: 0.0665 AC: 73817 AN: 1110472

Other (OTH) AF: 0.0998 AC: 6012 AN: 60242

GnomAD4 genome AF: 0.170 AC: 25776 AN: 151806 Hom.: 4059 Cov.: 31 AF XY: 0.167 AC XY: 12365 AN XY: 74194

African (AFR) AF: 0.421 AC: 17416 AN: 41342

American (AMR) AF: 0.0903 AC: 1379 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 458 AN: 3464

East Asian (EAS) AF: 0.0225 AC: 116 AN: 5152

South Asian (SAS) AF: 0.127 AC: 609 AN: 4810

European-Finnish (FIN) AF: 0.0567 AC: 597 AN: 10530

Middle Eastern (MID) AF: 0.195 AC: 57 AN: 292

European-Non Finnish (NFE) AF: 0.0704 AC: 4785 AN: 67936

Other (OTH) AF: 0.134 AC: 282 AN: 2104

Alfa AF: 0.0335 Hom.: 37

Bravo AF: 0.182

Asia WGS AF: 0.0960 AC: 335 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.48
PhyloP100		-0.062
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: rs7339; hg19: chr1-156108976; COSMIC: COSV61542559; COSMIC: COSV61542559;