rs10760450

Variant names:

• chr9-126697349-C-T
• rs10760450
• NM_001174147.2:c.*898C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001174147.2(LMX1B):​c.*898C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,402 control chromosomes in the GnomAD database, including 1,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1900 hom., cov: 32)
  • Exomes 𝑓: 0.12 (3 hom.)
• Consequence: LMX1B NM_001174147.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.351
• Publications: 7 publications found

Genes affected

LMX1B (HGNC:6654): (LIM homeobox transcription factor 1 beta) This gene encodes a member of LIM-homeodomain family of proteins containing two N-terminal zinc-binding LIM domains, 1 homeodomain, and a C-terminal glutamine-rich domain. It functions as a transcription factor, and is essential for the normal development of dorsal limb structures, the glomerular basement membrane, the anterior segment of the eye, and dopaminergic and serotonergic neurons. Mutations in this gene are associated with nail-patella syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

LMX1B Gene-Disease associations (from GenCC):

• nail-patella syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• nail-patella-like renal disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-126697349-C-T is Benign according to our data. Variant chr9-126697349-C-T is described in ClinVar as Benign. ClinVar VariationId is 364914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.*898C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.*898C>T		3_prime_UTR_variant	Exon 8 of 8		NP_001167617.1
LMX1B	NM_002316.4	c.*898C>T		3_prime_UTR_variant	Exon 8 of 8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.*898C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_001174147.2	ENSP00000362573.3
LMX1B	ENST00000355497.10	c.*898C>T		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000347684.5
LMX1B	ENST00000526117.6	c.*898C>T		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000436930.1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21058 AN: 152016 Hom.: 1902 Cov.: 32

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.131

GnomAD4 exome AF: 0.123 AC: 33 AN: 268 Hom.: 3 Cov.: 0 AF XY: 0.110 AC XY: 24 AN XY: 218

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: 8

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

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.250 AC: 3 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.124 AC: 27 AN: 218

Other (OTH) AF: 0.136 AC: 3 AN: 22

GnomAD4 genome AF: 0.138 AC: 21051 AN: 152134 Hom.: 1900 Cov.: 32 AF XY: 0.134 AC XY: 9959 AN XY: 74364

African (AFR) AF: 0.0476 AC: 1976 AN: 41528

American (AMR) AF: 0.110 AC: 1675 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 477 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5168

South Asian (SAS) AF: 0.103 AC: 498 AN: 4816

European-Finnish (FIN) AF: 0.170 AC: 1802 AN: 10600

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14277 AN: 67946

Other (OTH) AF: 0.129 AC: 273 AN: 2112

Alfa AF: 0.173 Hom.: 5058

Bravo AF: 0.128

Asia WGS AF: 0.0500 AC: 172 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nail-patella syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.3
DANN	Benign	0.72
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10760450; hg19: chr9-129459628;