12-25526118-A-G

Position:

• chr12-25526118-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001145728.2(LMNTD1):​c.779T>C​(p.Leu260Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMNTD1 NM_001145728.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

Genes affected

LMNTD1 (HGNC:26683): (lamin tail domain containing 1) Predicted to act upstream of or within cell population proliferation. Predicted to be located in nucleus. Predicted to be active in cytoplasm and nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNTD1	NM_001145728.2	c.779T>C	p.Leu260Pro	missense_variant	6/10	ENST00000458174.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNTD1	ENST00000458174.7	c.779T>C	p.Leu260Pro	missense_variant	6/10	2	NM_001145728.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000420 AC: 1 AN: 237988 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129026

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000572

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1446444 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719310

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.779T>C (p.L260P) alteration is located in exon 6 (coding exon 5) of the LMNTD1 gene. This alteration results from a T to C substitution at nucleotide position 779, causing the leucine (L) at amino acid position 260 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;T;T;T;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.7	D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;.;D;D;.
Vest4		0.84
MutPred		0.81		Gain of catalytic residue at K241 (P = 0);.;.;.;.;
MVP		0.73
MPC		1.2
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.91

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

LitVar

Other links and lift over

dbSNP: rs1368363450; hg19: chr12-25679052;