9-136196500-G-T

Position:

• chr9-136196500-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178138.6(LHX3):​c.*825C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00824 in 152,380 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LHX3 NM_178138.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.579

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-136196500-G-T is Benign according to our data. Variant chr9-136196500-G-T is described in ClinVar as [Benign]. Clinvar id is 365799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX3	NM_178138.6	c.*825C>A		3_prime_UTR_variant	6/6	ENST00000371748.10
LHX3	NM_001363746.1	c.*825C>A		3_prime_UTR_variant	6/6
LHX3	NM_014564.5	c.*825C>A		3_prime_UTR_variant	6/6
LHX3	XM_017015168.1	c.*825C>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX3	ENST00000371748.10	c.*825C>A		3_prime_UTR_variant	6/6	1	NM_178138.6
LHX3	ENST00000371746.9	c.*825C>A		3_prime_UTR_variant	6/6	1		P1
LHX3	ENST00000619587.1	c.*825C>A		3_prime_UTR_variant	6/6	1
LHX3	ENST00000645419.1	n.2844C>A		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 1249 AN: 152262 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.0899

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00669

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 436 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 254

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00824 AC: 1256 AN: 152380 Hom.: 29 Cov.: 33 AF XY: 0.0101 AC XY: 754 AN XY: 74512

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.00745

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0322

Gnomad4 SAS AF: 0.0894

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00476 Hom.: 1

Bravo AF: 0.00753

Asia WGS AF: 0.0700 AC: 241 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.4
DANN	Benign	0.84

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: rs3739470; hg19: chr9-139088346; COSMIC: COSV65583800;