9-136196545-G-A

Position:

• chr9-136196545-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_178138.6(LHX3):​c.*780C>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 0.0104 in 152,976 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.010 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (0 hom.)
• Consequence: LHX3 NM_178138.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.49

Genes affected

LHX3 (HGNC:6595): (LIM homeobox 3) This gene encodes a member of a large family of proteins which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor that is required for pituitary development and motor neuron specification. Mutations in this gene cause combined pituitary hormone deficiency 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1588/152388) while in subpopulation NFE AF= 0.0178 (1213/68036). AF 95% confidence interval is 0.017. There are 7 homozygotes in gnomad4. There are 736 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX3	NM_178138.6	c.*780C>T		3_prime_UTR_variant	6/6	ENST00000371748.10
LHX3	NM_001363746.1	c.*780C>T		3_prime_UTR_variant	6/6
LHX3	NM_014564.5	c.*780C>T		3_prime_UTR_variant	6/6
LHX3	XM_017015168.1	c.*780C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX3	ENST00000371748.10	c.*780C>T		3_prime_UTR_variant	6/6	1	NM_178138.6
LHX3	ENST00000371746.9	c.*780C>T		3_prime_UTR_variant	6/6	1		P1
LHX3	ENST00000619587.1	c.*780C>T		3_prime_UTR_variant	6/6	1
LHX3	ENST00000645419.1	n.2799C>T		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1588 AN: 152270 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.00602

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.00170 AC: 1 AN: 588 Hom.: 0 Cov.: 0 AF XY: 0.00269 AC XY: 1 AN XY: 372

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00296

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0104 AC: 1588 AN: 152388 Hom.: 7 Cov.: 33 AF XY: 0.00988 AC XY: 736 AN XY: 74530

Gnomad4 AFR AF: 0.00293

Gnomad4 AMR AF: 0.00712

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00602

Gnomad4 NFE AF: 0.0178

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0137 Hom.: 6

Bravo AF: 0.00977

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Non-acquired combined pituitary hormone deficiency with spine abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.18
DANN	Benign	0.42

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: rs4842130; hg19: chr9-139088391;