rs111537544

Variant names:

• chr11-72080605-G-A
• rs111537544
• ENST00000307198.11:c.-602G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-72080605-G-A
• chr11-72080605-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000307198.11(LRTOMT):​c.-602G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0063 in 152,298 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRTOMT ENST00000307198.11 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.358
• Publications: 2 publications found

Genes affected

LRTOMT (HGNC:25033): (leucine rich transmembrane and O-methyltransferase domain containing) This locus represents naturally occurring readthrough transcription between the neighboring LRRC51 (leucine-rich repeat containing 51) and TOMT (transmembrane O-methyltransferase) genes on chromosome 11. The readthrough transcript encodes a fusion protein that shares sequence identity with each individual gene product. Multiple reports implicate mutations in this gene in nonsyndromic deafness.[provided by RefSeq, Feb 2021]

LRRC51 (HGNC:55526): (leucine rich repeat containing 51) This gene belongs to the leucine-rich repeat containing family. The encoded protein contains a transmembrane domain and two leucine-rich repeat domains. Unlike in mouse and other mammals, readthrough transcription is observed in primates between this gene and the adjacent transmembrane O-methyltransferase (Tomt) gene. Previously, this locus was annotated as a single gene representing the readthrough transcripts as well as the two different transcript species that encoded different proteins. It has since been split into three genes, including the two stand-alone genes and a third gene representing the readthrough transcription. [provided by RefSeq, Feb 2022]

NUMA1 (HGNC:8059): (nuclear mitotic apparatus protein 1) This gene encodes a large protein that forms a structural component of the nuclear matrix. The encoded protein interacts with microtubules and plays a role in the formation and organization of the mitotic spindle during cell division. Chromosomal translocation of this gene with the RARA (retinoic acid receptor, alpha) gene on chromosome 17 have been detected in patients with acute promyelocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2013]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-72080605-G-A is Benign according to our data. Variant chr11-72080605-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 305975.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000307198.11. 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
	NUMA1	NM_006185.4	MANE Select	c.-250C>T		upstream_gene	N/A	NP_006176.2	Q14980-1
	LRRC51	NM_145309.6	MANE Select	c.-420G>A		upstream_gene	N/A	NP_660352.1	Q96E66-1
	NUMA1	NM_001286561.2		c.-348C>T		upstream_gene	N/A	NP_001273490.1	Q14980-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRTOMT	ENST00000307198.11	TSL:2	c.-602G>A		5_prime_UTR	Exon 1 of 7	ENSP00000305742.7
	LRRC51	ENST00000535883.6	TSL:1	n.-297G>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000437561.1	F5H6K5
	NUMA1	ENST00000543450.1	TSL:1	n.89C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00631 AC: 960 AN: 152180 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.0105

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 66 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 52

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.00630 AC: 960 AN: 152298 Hom.: 6 Cov.: 31 AF XY: 0.00557 AC XY: 415 AN XY: 74484

African (AFR) AF: 0.00156 AC: 65 AN: 41558

American (AMR) AF: 0.00699 AC: 107 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4832

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10606

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0102 AC: 693 AN: 68020

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00668

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Hearing loss, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.8
DANN	Benign	0.92
PhyloP100		-0.36
PromoterAI		0.036	Neutral
Mutation Taster		=300/0	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: rs111537544; hg19: chr11-71791651;