3-197999330-T-C

Position:

• chr3-197999330-T-C

Variant summary

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

The NM_001136049.3(LMLN):​c.1196T>C​(p.Met399Thr) 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: 33)
• Consequence: LMLN NM_001136049.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.58

Genes affected

LMLN (HGNC:15991): (leishmanolysin like peptidase) This gene encodes a zinc-metallopeptidase. The encoded protein may play a role in cell migration and invasion. Studies of a similar protein in Drosophila indicate a potential role in mitotic progression. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2009]

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, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMLN	NM_001136049.3	c.1196T>C	p.Met399Thr	missense_variant	11/17	ENST00000420910.7	NP_001129521.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMLN	ENST00000420910.7	c.1196T>C	p.Met399Thr	missense_variant	11/17	1	NM_001136049.3	ENSP00000410926

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

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

Dec 14, 2023

The c.1220T>C (p.M407T) alteration is located in exon 11 (coding exon 11) of the LMLN gene. This alteration results from a T to C substitution at nucleotide position 1220, causing the methionine (M) at amino acid position 407 to be replaced by a threonine (T). 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	0.88
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	.;D;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.1	.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.2	D;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.99	D;D;.;D
Vest4		0.89
MutPred		0.85		.;Loss of stability (P = 0.0662);Loss of stability (P = 0.0662);.;
MVP		0.75
MPC		1.0
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.81
gMVP		0.98

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: chr3-197726201;