chr9-136196743-C-T

Variant names:

• chr9-136196743-C-T
• rs879304888
• NM_178138.6:c.*582G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_178138.6(LHX3):​c.*582G>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 0.000317 in 154,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (0 hom.)
• Consequence: LHX3 NM_178138.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.21
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000309 (47/152226) while in subpopulation AMR AF = 0.00163 (25/15300). AF 95% confidence interval is 0.00114. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*582G>A		3_prime_UTR	Exon 6 of 6	NP_835258.1	Q9UBR4-1
	LHX3	NM_014564.5		c.*582G>A		3_prime_UTR	Exon 6 of 6	NP_055379.1	Q9UBR4-2
	LHX3	NM_001363746.1		c.*582G>A		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.*582G>A		3_prime_UTR	Exon 6 of 6	ENSP00000360813.4	Q9UBR4-1
	LHX3	ENST00000371746.9	TSL:1	c.*582G>A		3_prime_UTR	Exon 6 of 6	ENSP00000360811.3	Q9UBR4-2
	LHX3	ENST00000619587.1	TSL:1	c.*582G>A		3_prime_UTR	Exon 6 of 6	ENSP00000483080.1	F1T0D7

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000818 AC: 2 AN: 2444 Hom.: 0 Cov.: 0 AF XY: 0.000759 AC XY: 1 AN XY: 1318

African (AFR) AF: 0.00 AC: 0 AN: 10

American (AMR) AF: 0.00658 AC: 2 AN: 304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20

East Asian (EAS) AF: 0.00 AC: 0 AN: 178

South Asian (SAS) AF: 0.00 AC: 0 AN: 82

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1640

Other (OTH) AF: 0.00 AC: 0 AN: 82

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74422

African (AFR) AF: 0.0000241 AC: 1 AN: 41548

American (AMR) AF: 0.00163 AC: 25 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000540

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Non-acquired combined pituitary hormone deficiency with spine abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.20
DANN	Benign	0.43
PhyloP100		-1.2

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: rs879304888; hg19: chr9-139088589;