3-8537262-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP3 BP4_Moderate

The NM_014583.4(LMCD1):c.209G>C(p.Gly70Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000628 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: LMCD1 NM_014583.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.48

Genes affected

LMCD1 (HGNC:6633): (LIM and cysteine rich domains 1) This gene encodes a member of the LIM-domain family of zinc finger proteins. The encoded protein contains an N-terminal cysteine-rich domain and two C-terminal LIM domains. The presence of LIM domains suggests involvement in protein-protein interactions. The protein may act as a co-regulator of transcription along with other transcription factors. Alternate splicing results in multiple transcript variants of this gene. [provided by RefSeq, May 2013]

LMCD1-AS1 (HGNC:44477): (LMCD1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.15707144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMCD1	NM_014583.4	c.209G>C	p.Gly70Ala	missense_variant	3/6	ENST00000157600.8
LMCD1	NM_001278235.2	c.209G>C	p.Gly70Ala	missense_variant	3/5
LMCD1	NM_001278233.2	c.-11G>C		5_prime_UTR_variant	2/5
LMCD1	NM_001278234.2	c.51+4437G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMCD1	ENST00000157600.8	c.209G>C	p.Gly70Ala	missense_variant	3/6	1	NM_014583.4	P1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000705

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000358 AC: 90 AN: 251200 Hom.: 0 AF XY: 0.000368 AC XY: 50 AN XY: 135746

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000643

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000650 AC: 950 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.000615 AC XY: 447 AN XY: 727214

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000803

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74468

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000753 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000927

EpiControl AF: 0.000711

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

Aug 02, 2021

The c.209G>C (p.G70A) alteration is located in exon 3 (coding exon 3) of the LMCD1 gene. This alteration results from a G to C substitution at nucleotide position 209, causing the glycine (G) at amino acid position 70 to be replaced by an alanine (A). 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	Uncertain	0.066	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.2	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N;.;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.056	T;D;D
Polyphen		0.98	D;.;.
Vest4		0.86
MVP		0.98
MPC		1.0
ClinPred		0.19	T
GERP RS		4.6
Varity_R		0.32
gMVP		0.74

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: rs143907741; hg19: chr3-8578948;