rs2820312

Positions:

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

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045855343).
• BP6: Variant 1-201900129-G-A is Benign according to our data. Variant chr1-201900129-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMOD1	NM_012134.3	c.884C>T	p.Thr295Met	missense_variant	2/3	ENST00000367288.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMOD1	ENST00000367288.5	c.884C>T	p.Thr295Met	missense_variant	2/3	1	NM_012134.3	P1

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

GnomAD3 exomes AF: 0.278 AC: 69145 AN: 248924 Hom.: 10223 AF XY: 0.280 AC XY: 37807 AN XY: 135060

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 SAS exome AF: 0.282

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

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.256

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.302

Gnomad4 NFE exome AF: 0.335

Gnomad4 OTH exome AF: 0.293

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

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.265

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.328

Gnomad4 OTH AF: 0.245

Alfa AF: 0.300 Hom.: 17392

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 v4.3

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
MutationTaster	Benign	1.0	P
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

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