chr12-65169607-C-G

Variant names:

• chr12-65169607-C-G
• rs1592423587
• NM_014319.5:c.11C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014319.5(LEMD3):​c.11C>G​(p.Ala4Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LEMD3 NM_014319.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79
• Publications: 0 publications found

Genes affected

LEMD3 (HGNC:28887): (LEM domain containing 3) This locus encodes a LEM domain-containing protein. The encoded protein functions to antagonize transforming growth factor-beta signaling at the inner nuclear membrane. Two transcript variants encoding different isoforms have been found for this gene. Mutations in this gene have been associated with osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.[provided by RefSeq, Nov 2009]

LEMD3 Gene-Disease associations (from GenCC):

• Buschke-Ollendorff syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• isolated osteopoikilosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melorheostosis with osteopoikilosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289319 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3014896).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014319.5. 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
	LEMD3	NM_014319.5	MANE Select	c.11C>G	p.Ala4Gly	missense	Exon 1 of 13	NP_055134.2
	LEMD3	NM_001167614.2		c.11C>G	p.Ala4Gly	missense	Exon 1 of 13	NP_001161086.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEMD3	ENST00000308330.3	TSL:1 MANE Select	c.11C>G	p.Ala4Gly	missense	Exon 1 of 13	ENSP00000308369.2	Q9Y2U8
	LEMD3	ENST00000883212.1		c.11C>G	p.Ala4Gly	missense	Exon 1 of 13	ENSP00000553271.1
	LEMD3	ENST00000935241.1		c.11C>G	p.Ala4Gly	missense	Exon 1 of 13	ENSP00000605300.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.037	D
Polyphen		0.99	D
Vest4		0.34
MutPred		0.19		Loss of helix (P = 0.0068)
MVP		0.41
ClinPred		0.68	D
GERP RS		4.0
PromoterAI		-0.11	Neutral
Varity_R		0.31
gMVP		0.44
Mutation Taster		=95/5	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: rs1592423587; hg19: chr12-65563387;