rs777696417

Positions:

• chr1-201899905-G-A
• chr1-201899905-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_012134.3(LMOD1):​c.1108C>T​(p.Arg370Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LMOD1 NM_012134.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.83

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-201899905-G-A is Pathogenic according to our data. Variant chr1-201899905-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 264986.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD1	NM_012134.3	c.1108C>T	p.Arg370Ter	stop_gained	2/3	ENST00000367288.5	NP_036266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD1	ENST00000367288.5	c.1108C>T	p.Arg370Ter	stop_gained	2/3	1	NM_012134.3	ENSP00000356257	P1
	ENST00000414927.5	n.421G>A		non_coding_transcript_exon_variant	3/3	3
	ENST00000458139.1	n.527G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456620 Hom.: 0 Cov.: 39 AF XY: 0.00000276 AC XY: 2 AN XY: 724440

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Megacystis-microcolon-intestinal hypoperistalsis syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 02, 2021

- -

Visceral myopathy 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genetics, Erasmus University Medical Center

Sep 15, 2016

Loss of protein. Functional experiments described in manuscript. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A
Vest4		0.41
GERP RS		3.7

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: rs777696417; hg19: chr1-201869033;