rs11103377

Variant names:

• chr9-136205289-A-G
• rs11103377
• NM_178138.6:c.-277T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_178138.6(LHX3):​c.-277T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 151,630 control chromosomes in the GnomAD database, including 16,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.46 (16613 hom., cov: 31)
• Consequence: LHX3 NM_178138.6 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.80
• Publications: 6 publications found

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]

LHX3 Gene-Disease associations (from GenCC):

• non-acquired combined pituitary hormone deficiency with spine abnormalities

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hypothyroidism due to deficient transcription factors involved in pituitary development or function

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-136205289-A-G is Benign according to our data. Variant chr9-136205289-A-G is described in ClinVar as Benign. ClinVar VariationId is 1288710.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX3	NM_178138.6	c.-277T>C		upstream_gene_variant		ENST00000371748.10	NP_835258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX3	ENST00000371748.10	c.-277T>C		upstream_gene_variant		1	NM_178138.6	ENSP00000360813.4

Frequencies

GnomAD3 genomes AF: 0.461 AC: 69829 AN: 151514 Hom.: 16613 Cov.: 31

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.464

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.475

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.461 AC: 69843 AN: 151630 Hom.: 16613 Cov.: 31 AF XY: 0.456 AC XY: 33787 AN XY: 74114

African (AFR) AF: 0.380 AC: 15729 AN: 41340

American (AMR) AF: 0.427 AC: 6522 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 1610 AN: 3470

East Asian (EAS) AF: 0.356 AC: 1817 AN: 5100

South Asian (SAS) AF: 0.420 AC: 2023 AN: 4814

European-Finnish (FIN) AF: 0.435 AC: 4577 AN: 10516

Middle Eastern (MID) AF: 0.528 AC: 152 AN: 288

European-Non Finnish (NFE) AF: 0.530 AC: 35922 AN: 67800

Other (OTH) AF: 0.472 AC: 995 AN: 2106

Alfa AF: 0.483 Hom.: 2238

Bravo AF: 0.456

Asia WGS AF: 0.382 AC: 1326 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.0
DANN	Benign	0.36
PhyloP100		-1.8
PromoterAI		-0.013	Neutral

Splicing

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

Other links and lift over

dbSNP: rs11103377; hg19: chr9-139097135;