9-136203032-G-C

Variant names:

• chr9-136203032-G-C
• ENST00000371746.9:c.8C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014564.5(LHX3):​c.8C>G​(p.Ala3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000731 in 1,367,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: LHX3 NM_014564.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4112885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX3	NM_178138.6	c.79+1902C>G		intron_variant	Intron 1 of 5	ENST00000371748.10	NP_835258.1
LHX3	NM_014564.5	c.8C>G	p.Ala3Gly	missense_variant	Exon 1 of 6		NP_055379.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX3	ENST00000371746.9	c.8C>G	p.Ala3Gly	missense_variant	Exon 1 of 6	1		ENSP00000360811.3
LHX3	ENST00000371748.10	c.79+1902C>G		intron_variant	Intron 1 of 5	1	NM_178138.6	ENSP00000360813.4
LHX3	ENST00000645419.1	n.117C>G		non_coding_transcript_exon_variant	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1367382 Hom.: 0 Cov.: 35 AF XY: 0.00000148 AC XY: 1 AN XY: 674638

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.32e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.033	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.16
MutPred		0.32		Loss of relative solvent accessibility (P = 0.0186);
MVP		0.87
MPC		1.9
ClinPred		0.98	D
GERP RS		3.4
gMVP		0.44

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-139094878;