12-113471470-C-G

Variant names:

• chr12-113471470-C-G
• rs187043986
• NM_022363.3:c.29G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022363.3(LHX5):​c.29G>C​(p.Arg10Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R10L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LHX5 NM_022363.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.15
• Publications: 0 publications found

Genes affected

LHX5 (HGNC:14216): (LIM homeobox 5) This gene encodes a protein belonging to a large protein family, members of which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein may function as a transcriptional regulator and be involved in the control of differentiation and development of the forebrain. In mice, this protein is essential for the regulation of precursor cell proliferation and the control of neuronal differentiation and migration during hippocampal development. This protein is involved in learning and motor functions in adult mice. [provided by RefSeq, Jul 2008]

LHX5-AS1 (HGNC:49570): (LHX5 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022363.3. 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
	LHX5	NM_022363.3	MANE Select	c.29G>C	p.Arg10Pro	missense	Exon 1 of 5	NP_071758.1	Q9H2C1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX5	ENST00000261731.4	TSL:1 MANE Select	c.29G>C	p.Arg10Pro	missense	Exon 1 of 5	ENSP00000261731.2	Q9H2C1
	LHX5-AS1	ENST00000743755.1		n.255+3646C>G		intron	N/A
	LHX5-AS1	ENST00000743756.1		n.301+868C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456250 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723960

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.00 AC: 0 AN: 85338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109578

Other (OTH) AF: 0.00 AC: 0 AN: 60142

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.028	D
Polyphen		0.99	D
Vest4		0.64
MutPred		0.51		Gain of catalytic residue at A6 (P = 0)
MVP		0.95
ClinPred		0.98	D
GERP RS		4.0
PromoterAI		-0.019	Neutral
Varity_R		0.78
gMVP		0.94
Mutation Taster		=19/81	disease causing

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: rs187043986; hg19: chr12-113909275;