9-126699435-C-T

Variant names:

• chr9-126699435-C-T
• rs4083644
• NM_001174147.2:c.*2984C>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.*2984C>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 0.269 in 152,136 control chromosomes in the GnomAD database, including 5,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5538 hom., cov: 32)
  • Exomes 𝑓: 0.28 (1 hom.)
• Consequence: LMX1B NM_001174147.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.319
• Publications: 6 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=-0.84).
• BP6: Variant 9-126699435-C-T is Benign according to our data. Variant chr9-126699435-C-T is described in ClinVar as Benign. ClinVar VariationId is 364961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174147.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMX1B	NM_001174147.2	MANE Select	c.*2984C>T		3_prime_UTR	Exon 8 of 8	NP_001167618.1
	LMX1B	NM_001174146.2		c.*2984C>T		3_prime_UTR	Exon 8 of 8	NP_001167617.1
	LMX1B	NM_002316.4		c.*2984C>T		3_prime_UTR	Exon 8 of 8	NP_002307.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMX1B	ENST00000373474.9	TSL:1 MANE Select	c.*2984C>T		3_prime_UTR	Exon 8 of 8	ENSP00000362573.3
	LMX1B	ENST00000355497.10	TSL:1	c.*2984C>T		3_prime_UTR	Exon 8 of 8	ENSP00000347684.5
	LMX1B	ENST00000526117.6	TSL:1	c.*2984C>T		3_prime_UTR	Exon 8 of 8	ENSP00000436930.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40827 AN: 151982 Hom.: 5535 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.278 AC: 10 AN: 36 Hom.: 1 Cov.: 0 AF XY: 0.250 AC XY: 8 AN XY: 32

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.300 AC: 9 AN: 30

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

GnomAD4 genome AF: 0.269 AC: 40875 AN: 152100 Hom.: 5538 Cov.: 32 AF XY: 0.271 AC XY: 20168 AN XY: 74348

African (AFR) AF: 0.245 AC: 10152 AN: 41518

American (AMR) AF: 0.211 AC: 3222 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1290 AN: 3472

East Asian (EAS) AF: 0.284 AC: 1466 AN: 5166

South Asian (SAS) AF: 0.370 AC: 1787 AN: 4824

European-Finnish (FIN) AF: 0.278 AC: 2941 AN: 10566

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19028 AN: 67952

Other (OTH) AF: 0.269 AC: 569 AN: 2112

Alfa AF: 0.275 Hom.: 1791

Bravo AF: 0.256

Asia WGS AF: 0.359 AC: 1248 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.5
DANN	Benign	0.76
PhyloP100		0.32
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: rs4083644; hg19: chr9-129461714;