11-558701-A-C

Variant names:

• chr11-558701-A-C
• rs771320992
• NM_173573.3:c.224T>G

Variant summary

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

The NM_173573.3(LMNTD2):​c.224T>G​(p.Ile75Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,070 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. I75N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LMNTD2 NM_173573.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.665
• Publications: 0 publications found

Genes affected

LMNTD2 (HGNC:28561): (lamin tail domain containing 2) Predicted to be a structural constituent of chromatin. Predicted to be involved in regulation of chromatin assembly. Predicted to act upstream of or within positive regulation of mRNA splicing, via spliceosome. Predicted to be active in lamin filament. [provided by Alliance of Genome Resources, Apr 2022]

LMNTD2-AS1 (HGNC:41204): (LMNTD2 antisense RNA 1)

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 (MetaRNN=0.25305107).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173573.3. 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
	LMNTD2	NM_173573.3	MANE Select	c.224T>G	p.Ile75Ser	missense	Exon 3 of 14	NP_775844.2	Q8IXW0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNTD2	ENST00000329451.8	TSL:1 MANE Select	c.224T>G	p.Ile75Ser	missense	Exon 3 of 14	ENSP00000331167.3	Q8IXW0
	LMNTD2	ENST00000886189.1		c.224T>G	p.Ile75Ser	missense	Exon 3 of 14	ENSP00000556248.1
	LMNTD2	ENST00000886190.1		c.242T>G	p.Ile81Ser	missense	Exon 3 of 14	ENSP00000556249.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454070 Hom.: 0 Cov.: 45 AF XY: 0.00000277 AC XY: 2 AN XY: 722910

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 43704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39454

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5200

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109482

Other (OTH) AF: 0.00 AC: 0 AN: 60034

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.75	T
PhyloP100		0.67
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.26		Gain of disorder (P = 0.0075)
MVP		0.54
MPC		0.47
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.64
gMVP		0.59
Mutation Taster		=84/16	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: rs771320992; hg19: chr11-558701;