NM_005029.4:c.703G>A

Variant names:

• chr10-102230720-C-T
• rs148445461
• NM_005029.4:c.703G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_005029.4(PITX3):​c.703G>A​(p.Val235Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,540,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: PITX3 NM_005029.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.29
• Publications: 1 publications found

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:4181): (golgi brefeldin A resistant guanine nucleotide exchange factor 1) This gene encodes a member of the Sec7 domain family. The encoded protein is a guanine nucleotide exchange factor that regulates the recruitment of proteins to membranes by mediating GDP to GTP exchange. The encoded protein is localized to the Golgi apparatus and plays a role in vesicular trafficking by activating ADP ribosylation factor 1. The encoded protein has also been identified as an important host factor for viral replication. Multiple transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

GBF1 Gene-Disease associations (from GenCC):

• axonal neuropathy

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.4984 (below the threshold of 3.09). Trascript score misZ: 0.65179 (below the threshold of 3.09). GenCC associations: The gene is linked to cataract 11 multiple types, cataract-glaucoma syndrome, early-onset posterior polar cataract, anterior segment dysgenesis 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.067524165).
• BP6: Variant 10-102230720-C-T is Benign according to our data. Variant chr10-102230720-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2635698.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000224 (34/151880) while in subpopulation NFE AF = 0.000427 (29/67894). AF 95% confidence interval is 0.000305. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 34 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005029.4. 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
	PITX3	NM_005029.4	MANE Select	c.703G>A	p.Val235Met	missense	Exon 4 of 4	NP_005020.1	O75364
	GBF1	NM_001391923.1		c.-207C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 40	NP_001378852.1	Q92538-2
	GBF1	NM_001391924.1		c.-345C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 41	NP_001378853.1	Q92538-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX3	ENST00000370002.8	TSL:1 MANE Select	c.703G>A	p.Val235Met	missense	Exon 4 of 4	ENSP00000359019.3	O75364

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151772 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00441

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000101 AC: 14 AN: 138408 AF XY: 0.0000538

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000208 AC: 289 AN: 1388838 Hom.: 0 Cov.: 32 AF XY: 0.000194 AC XY: 133 AN XY: 684890

African (AFR) AF: 0.00 AC: 0 AN: 30526

American (AMR) AF: 0.0000290 AC: 1 AN: 34534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24672

East Asian (EAS) AF: 0.00 AC: 0 AN: 35018

South Asian (SAS) AF: 0.00 AC: 0 AN: 78196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5138

European-Non Finnish (NFE) AF: 0.000261 AC: 281 AN: 1075122

Other (OTH) AF: 0.000122 AC: 7 AN: 57496

GnomAD4 genome AF: 0.000224 AC: 34 AN: 151880 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74250

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000427 AC: 29 AN: 67894

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000250 AC: 2

ExAC AF: 0.0000760 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	-	1	not specified (1)
-	1	-	PITX3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.068	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.3
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.28
Sift	Benign	0.039	D
Sift4G	Uncertain	0.053	T
Polyphen		0.95	P
Vest4		0.44
MVP		0.56
MPC		0.85
ClinPred		0.22	T
GERP RS		5.0
Varity_R		0.18
gMVP		0.52
Mutation Taster		=93/7	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: rs148445461; hg19: chr10-103990477;