9-136196824-T-C

Variant names:

• chr9-136196824-T-C
• rs886063698
• NM_178138.6:c.*501A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178138.6(LHX3):​c.*501A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LHX3 NM_178138.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34
• Publications: 0 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• hypothyroidism due to deficient transcription factors involved in pituitary development or function

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178138.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX3	NM_178138.6	MANE Select	c.*501A>G		3_prime_UTR	Exon 6 of 6	NP_835258.1	Q9UBR4-1
	LHX3	NM_014564.5		c.*501A>G		3_prime_UTR	Exon 6 of 6	NP_055379.1	Q9UBR4-2
	LHX3	NM_001363746.1		c.*501A>G		3_prime_UTR	Exon 6 of 6	NP_001350675.1	F1T0D7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX3	ENST00000371748.10	TSL:1 MANE Select	c.*501A>G		3_prime_UTR	Exon 6 of 6	ENSP00000360813.4	Q9UBR4-1
	LHX3	ENST00000371746.9	TSL:1	c.*501A>G		3_prime_UTR	Exon 6 of 6	ENSP00000360811.3	Q9UBR4-2
	LHX3	ENST00000619587.1	TSL:1	c.*501A>G		3_prime_UTR	Exon 6 of 6	ENSP00000483080.1	F1T0D7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 20038 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10196

African (AFR) AF: 0.00 AC: 0 AN: 168

American (AMR) AF: 0.00 AC: 0 AN: 1918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 352

East Asian (EAS) AF: 0.00 AC: 0 AN: 982

South Asian (SAS) AF: 0.00 AC: 0 AN: 1942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 64

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 12976

Other (OTH) AF: 0.00 AC: 0 AN: 1096

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.87
DANN	Benign	0.67
PhyloP100		-2.3

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

Other links and lift over

dbSNP: rs886063698; hg19: chr9-139088670;