NM_014319.5:c.6G>C

Variant names:

• chr12-65169602-G-C
• rs1868436630
• NM_014319.5:c.6G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014319.5(LEMD3):​c.6G>C​(p.Ala2Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.000000697 in 1,435,554 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. Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: LEMD3 NM_014319.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.02
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).

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.6G>C	p.Ala2Ala	synonymous	Exon 1 of 13	NP_055134.2
	LEMD3	NM_001167614.2		c.6G>C	p.Ala2Ala	synonymous	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.6G>C	p.Ala2Ala	synonymous	Exon 1 of 13	ENSP00000308369.2	Q9Y2U8
	LEMD3	ENST00000883212.1		c.6G>C	p.Ala2Ala	synonymous	Exon 1 of 13	ENSP00000553271.1
	LEMD3	ENST00000935241.1		c.6G>C	p.Ala2Ala	synonymous	Exon 1 of 13	ENSP00000605300.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435554 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 711706

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33196

American (AMR) AF: 0.00 AC: 0 AN: 40272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25616

East Asian (EAS) AF: 0.00 AC: 0 AN: 38872

South Asian (SAS) AF: 0.00 AC: 0 AN: 82754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4116

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101242

Other (OTH) AF: 0.00 AC: 0 AN: 59312

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		6.0
PromoterAI		-0.29	Neutral

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: rs1868436630; hg19: chr12-65563382;