rs2820312

Variant names:

• chr1-201900129-G-A
• rs2820312
• NM_012134.3:c.884C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-201900129-G-A
• chr1-201900129-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012134.3(LMOD1):​c.884C>T​(p.Thr295Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,613,506 control chromosomes in the GnomAD database, including 80,997 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. T295S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.28 (6065 hom., cov: 31)
  • Exomes 𝑓: 0.31 (74932 hom.)
• Consequence: LMOD1 NM_012134.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115
• Publications: 46 publications found

Genes affected

LMOD1 (HGNC:6647): (leiomodin 1) The leiomodin 1 protein has a putative membrane-spanning region and 2 types of tandemly repeated blocks. The transcript is expressed in all tissues tested, with the highest levels in thyroid, eye muscle, skeletal muscle, and ovary. Increased expression of leiomodin 1 may be linked to Graves' disease and thyroid-associated ophthalmopathy. [provided by RefSeq, Jul 2008]

LMOD1 Gene-Disease associations (from GenCC):

• megacystis-microcolon-intestinal hypoperistalsis syndrome 3

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000223774 (HGNC:58701):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045855343).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012134.3. 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
	LMOD1	NM_012134.3	MANE Select	c.884C>T	p.Thr295Met	missense	Exon 2 of 3	NP_036266.2	P29536-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD1	ENST00000367288.5	TSL:1 MANE Select	c.884C>T	p.Thr295Met	missense	Exon 2 of 3	ENSP00000356257.4	P29536-1
	LMOD1	ENST00000869075.1		c.262-1731C>T		intron	N/A	ENSP00000539134.1
	ENSG00000223774	ENST00000414927.5	TSL:3	n.*151G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42009 AN: 151862 Hom.: 6062 Cov.: 31

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.278 AC: 69145 AN: 248924 AF XY: 0.280

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.106

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.314 AC: 459377 AN: 1461524 Hom.: 74932 Cov.: 57 AF XY: 0.313 AC XY: 227470 AN XY: 727054

African (AFR) AF: 0.216 AC: 7236 AN: 33480

American (AMR) AF: 0.256 AC: 11455 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 5007 AN: 26136

East Asian (EAS) AF: 0.102 AC: 4060 AN: 39698

South Asian (SAS) AF: 0.281 AC: 24270 AN: 86256

European-Finnish (FIN) AF: 0.302 AC: 16129 AN: 53388

Middle Eastern (MID) AF: 0.203 AC: 1171 AN: 5768

European-Non Finnish (NFE) AF: 0.335 AC: 372332 AN: 1111736

Other (OTH) AF: 0.293 AC: 17717 AN: 60372

GnomAD4 genome AF: 0.277 AC: 42025 AN: 151982 Hom.: 6065 Cov.: 31 AF XY: 0.274 AC XY: 20382 AN XY: 74298

African (AFR) AF: 0.219 AC: 9070 AN: 41454

American (AMR) AF: 0.265 AC: 4053 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 657 AN: 3468

East Asian (EAS) AF: 0.103 AC: 531 AN: 5160

South Asian (SAS) AF: 0.261 AC: 1253 AN: 4802

European-Finnish (FIN) AF: 0.313 AC: 3303 AN: 10564

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22264 AN: 67942

Other (OTH) AF: 0.245 AC: 516 AN: 2110

Alfa AF: 0.296 Hom.: 23772

Bravo AF: 0.270

TwinsUK AF: 0.323 AC: 1199

ALSPAC AF: 0.330 AC: 1273

ESP6500AA AF: 0.206 AC: 830

ESP6500EA AF: 0.314 AC: 2618

ExAC AF: 0.278 AC: 33662

Asia WGS AF: 0.160 AC: 555 AN: 3478

EpiCase AF: 0.315

EpiControl AF: 0.311

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	3.8
DANN	Benign	0.86
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.12
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.24
Sift	Benign	0.29	T
Sift4G	Benign	0.093	T
Polyphen		0.95	P
Vest4		0.028
MPC		0.40
ClinPred		0.0023	T
GERP RS		0.58
Varity_R		0.016
gMVP		0.12
Mutation Taster		=100/0	polymorphism (auto)

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: rs2820312; hg19: chr1-201869257; COSMIC: COSV66172120; COSMIC: COSV66172120;