12-65169612-G-C

Variant names:

• chr12-65169612-G-C
• rs1162532082
• NM_014319.5:c.16G>C

Variant summary

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

The NM_014319.5(LEMD3):​c.16G>C​(p.Ala6Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,435,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. A6S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: LEMD3 NM_014319.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.84
• 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=0.35130218).

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.16G>C	p.Ala6Pro	missense	Exon 1 of 13	NP_055134.2
	LEMD3	NM_001167614.2		c.16G>C	p.Ala6Pro	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.16G>C	p.Ala6Pro	missense	Exon 1 of 13	ENSP00000308369.2	Q9Y2U8
	LEMD3	ENST00000883212.1		c.16G>C	p.Ala6Pro	missense	Exon 1 of 13	ENSP00000553271.1
	LEMD3	ENST00000935241.1		c.16G>C	p.Ala6Pro	missense	Exon 1 of 13	ENSP00000605300.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435796 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 711926

African (AFR) AF: 0.00 AC: 0 AN: 33190

American (AMR) AF: 0.00 AC: 0 AN: 40160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25632

East Asian (EAS) AF: 0.00 AC: 0 AN: 38874

South Asian (SAS) AF: 0.00 AC: 0 AN: 82844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4140

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101456

Other (OTH) AF: 0.00 AC: 0 AN: 59344

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.23		Loss of helix (P = 0.0033)
MVP		0.39
ClinPred		0.79	D
GERP RS		4.0
PromoterAI		-0.19	Neutral
Varity_R		0.48
gMVP		0.57
Mutation Taster		=85/15	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: rs1162532082; hg19: chr12-65563392;