10-102231624-G-C

Position:

• chr10-102231624-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005029.4(PITX3):​c.285C>G​(p.Ile95Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,546 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. Synonymous variant affecting the same amino acid position (i.e. I95I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PITX3 NM_005029.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215

Genes affected

PITX3 (HGNC:9006): (paired like homeodomain 3) This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family act as transcription factors. This protein is involved in lens formation during eye development. Mutations of this gene have been associated with anterior segment mesenchymal dysgenesis and congenital cataracts. [provided by RefSeq, Jul 2008]

GBF1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITX3	NM_005029.4	c.285C>G	p.Ile95Met	missense_variant	3/4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1	c.285C>G	p.Ile95Met	missense_variant	2/3		XP_047281308.1
GBF1	NM_001391923.1	c.-11+708G>C		intron_variant			NP_001378852.1
GBF1	NM_001391924.1	c.-149+708G>C		intron_variant			NP_001378853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITX3	ENST00000370002.8	c.285C>G	p.Ile95Met	missense_variant	3/4	1	NM_005029.4	ENSP00000359019	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457546 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 724850

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Benign	0.19
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.95	D;.
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.76		Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);
MVP		0.91
MPC		1.8
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.86
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2281983; hg19: chr10-103991381;