rs572411652

Variant names:

• chr9-136196535-G-A
• rs572411652
• NM_178138.6:c.*790C>T

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.*790C>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 0.000696 in 152,390 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 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LHX3 NM_178138.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.72
• 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=-0.98).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000696 (106/152390) while in subpopulation AMR AF = 0.00163 (25/15312). AF 95% confidence interval is 0.00113. There are 0 homozygotes in GnomAd4. There are 46 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.*790C>T		3_prime_UTR	Exon 6 of 6	NP_835258.1	Q9UBR4-1
	LHX3	NM_014564.5		c.*790C>T		3_prime_UTR	Exon 6 of 6	NP_055379.1	Q9UBR4-2
	LHX3	NM_001363746.1		c.*790C>T		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.*790C>T		3_prime_UTR	Exon 6 of 6	ENSP00000360813.4	Q9UBR4-1
	LHX3	ENST00000371746.9	TSL:1	c.*790C>T		3_prime_UTR	Exon 6 of 6	ENSP00000360811.3	Q9UBR4-2
	LHX3	ENST00000619587.1	TSL:1	c.*790C>T		3_prime_UTR	Exon 6 of 6	ENSP00000483080.1	F1T0D7

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152272 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 564 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 356

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 110

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 338

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 90

Other (OTH) AF: 0.00 AC: 0 AN: 14

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152390 Hom.: 0 Cov.: 33 AF XY: 0.000617 AC XY: 46 AN XY: 74524

African (AFR) AF: 0.000216 AC: 9 AN: 41594

American (AMR) AF: 0.00163 AC: 25 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68042

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000688 Hom.: 0

Bravo AF: 0.000733

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	-0.98
CADD	Benign	0.17
DANN	Benign	0.50
PhyloP100		-3.7

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: rs572411652; hg19: chr9-139088381;