chr1-156129878-T-A

Variant names:

• chr1-156129878-T-A
• NM_170707.4:c.357-739T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001406988.1(LMNA):​c.29T>A​(p.Leu10Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000162 in 617,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L10R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: LMNA NM_001406988.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.357-739T>A		intron_variant	Intron 1 of 11	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.357-739T>A		intron_variant	Intron 1 of 9	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.357-739T>A		intron_variant	Intron 1 of 11	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.357-739T>A		intron_variant	Intron 1 of 9		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000162 AC: 1 AN: 617972 Hom.: 0 Cov.: 0 AF XY: 0.00000298 AC XY: 1 AN XY: 336096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	0.10
Eigen_PC	Benign	-0.014
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.25	D
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Vest4		0.47
MutPred		0.74		Gain of disorder (P = 0.1453);
MVP		0.61
ClinPred		0.80	D
GERP RS		4.4

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-156099669;