rs3739470

Variant names:

• chr9-136196500-G-T
• rs3739470
• NM_178138.6:c.*825C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178138.6(LHX3):​c.*825C>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 0.00824 in 152,380 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LHX3 NM_178138.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.579
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-136196500-G-T is Benign according to our data. Variant chr9-136196500-G-T is described in ClinVar as Benign. ClinVar VariationId is 365799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0824 is higher than 0.05.

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.*825C>A		3_prime_UTR	Exon 6 of 6	NP_835258.1	Q9UBR4-1
	LHX3	NM_014564.5		c.*825C>A		3_prime_UTR	Exon 6 of 6	NP_055379.1	Q9UBR4-2
	LHX3	NM_001363746.1		c.*825C>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.*825C>A		3_prime_UTR	Exon 6 of 6	ENSP00000360813.4	Q9UBR4-1
	LHX3	ENST00000371746.9	TSL:1	c.*825C>A		3_prime_UTR	Exon 6 of 6	ENSP00000360811.3	Q9UBR4-2
	LHX3	ENST00000619587.1	TSL:1	c.*825C>A		3_prime_UTR	Exon 6 of 6	ENSP00000483080.1	F1T0D7

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 1249 AN: 152262 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.0899

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00669

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 436 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 254

African (AFR) AC: 0 AN: 0

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 108

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 286

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 32

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.00824 AC: 1256 AN: 152380 Hom.: 29 Cov.: 33 AF XY: 0.0101 AC XY: 754 AN XY: 74512

African (AFR) AF: 0.0113 AC: 468 AN: 41598

American (AMR) AF: 0.00745 AC: 114 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0322 AC: 167 AN: 5192

South Asian (SAS) AF: 0.0894 AC: 431 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68036

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00476 Hom.: 1

Bravo AF: 0.00753

Asia WGS AF: 0.0700 AC: 241 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Non-acquired combined pituitary hormone deficiency with spine abnormalities (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.4
DANN	Benign	0.84
PhyloP100		0.58
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: rs3739470; hg19: chr9-139088346; COSMIC: COSV65583800;