chr12-65169633-T-C

Variant names:

• chr12-65169633-T-C
• rs952563919
• NM_014319.5:c.37T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014319.5(LEMD3):​c.37T>C​(p.Ser13Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,437,494 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LEMD3 NM_014319.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.42

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]

ENSG00000289319 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEMD3	NM_014319.5	c.37T>C	p.Ser13Pro	missense_variant	Exon 1 of 13	ENST00000308330.3	NP_055134.2
LEMD3	NM_001167614.2	c.37T>C	p.Ser13Pro	missense_variant	Exon 1 of 13		NP_001161086.1
LOC124902953	XR_007063349.1	n.-217A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEMD3	ENST00000308330.3	c.37T>C	p.Ser13Pro	missense_variant	Exon 1 of 13	1	NM_014319.5	ENSP00000308369.2
LEMD3	ENST00000541171.1	n.51T>C		non_coding_transcript_exon_variant	Exon 1 of 2	2
ENSG00000289319	ENST00000685904.1	n.-171A>G		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000972 AC: 2 AN: 205742 Hom.: 0 AF XY: 0.00000889 AC XY: 1 AN XY: 112426

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000108

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1437494 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 712962

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: 0.0000120

Gnomad4 FIN exome AF: 0.0000397

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.0061
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.022	D
Polyphen		0.43	B
Vest4		0.49
MutPred		0.48		Loss of phosphorylation at S13 (P = 0.0255);
MVP		0.85
ClinPred		0.80	D
GERP RS		1.5
Varity_R		0.63
gMVP		0.58

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: rs952563919; hg19: chr12-65563413;