rs4842130

Variant names:

• chr9-136196545-G-A
• rs4842130
• NM_178138.6:c.*780C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_178138.6(LHX3):​c.*780C>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 0.0104 in 152,976 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.010 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (0 hom.)
• Consequence: LHX3 NM_178138.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.49
• Publications: 2 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0104 (1588/152388) while in subpopulation NFE AF = 0.0178 (1213/68036). AF 95% confidence interval is 0.017. There are 7 homozygotes in GnomAd4. There are 736 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
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

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.*780C>T		3_prime_UTR	Exon 6 of 6	NP_835258.1	Q9UBR4-1
	LHX3	NM_014564.5		c.*780C>T		3_prime_UTR	Exon 6 of 6	NP_055379.1	Q9UBR4-2
	LHX3	NM_001363746.1		c.*780C>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.*780C>T		3_prime_UTR	Exon 6 of 6	ENSP00000360813.4	Q9UBR4-1
	LHX3	ENST00000371746.9	TSL:1	c.*780C>T		3_prime_UTR	Exon 6 of 6	ENSP00000360811.3	Q9UBR4-2
	LHX3	ENST00000619587.1	TSL:1	c.*780C>T		3_prime_UTR	Exon 6 of 6	ENSP00000483080.1	F1T0D7

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1588 AN: 152270 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.00602

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.00170 AC: 1 AN: 588 Hom.: 0 Cov.: 0 AF XY: 0.00269 AC XY: 1 AN XY: 372

African (AFR) AF: 0.00 AC: 0 AN: 4

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: 116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00296 AC: 1 AN: 338

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 104

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

GnomAD4 genome AF: 0.0104 AC: 1588 AN: 152388 Hom.: 7 Cov.: 33 AF XY: 0.00988 AC XY: 736 AN XY: 74530

African (AFR) AF: 0.00293 AC: 122 AN: 41594

American (AMR) AF: 0.00712 AC: 109 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4832

European-Finnish (FIN) AF: 0.00602 AC: 64 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0178 AC: 1213 AN: 68036

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0137 Hom.: 6

Bravo AF: 0.00977

Asia WGS AF: 0.00289 AC: 10 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	-0.86
CADD	Benign	0.18
DANN	Benign	0.42
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

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: rs4842130; hg19: chr9-139088391;