rs104894175

Variant names:

• chr10-102232043-C-T
• rs104894175
• NM_005029.4:c.38G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_005029.4(PITX3):​c.38G>A​(p.Ser13Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,452,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PITX3 NM_005029.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.53
• Publications: 19 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 10-102232043-C-T is Pathogenic according to our data. Variant chr10-102232043-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 6938.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX3	NM_005029.4	MANE Select	c.38G>A	p.Ser13Asn	missense	Exon 2 of 4	NP_005020.1
	GBF1	NM_001391923.1		c.-11+1127C>T		intron	N/A	NP_001378852.1
	GBF1	NM_001391924.1		c.-149+1127C>T		intron	N/A	NP_001378853.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX3	ENST00000370002.8	TSL:1 MANE Select	c.38G>A	p.Ser13Asn	missense	Exon 2 of 4	ENSP00000359019.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228724 AF XY: 0.00000794

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: 0.00000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1452624 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722612

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 85618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110108

Other (OTH) AF: 0.00 AC: 0 AN: 60108

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cataract 11 multiple types (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	0.000058	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.81	L
PhyloP100		6.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.46
Sift	Benign	0.38	T
Sift4G	Benign	0.51	T
Polyphen		0.98	D
Vest4		0.58
MVP		0.73
MPC		1.2
ClinPred		0.86	D
GERP RS		5.6
PromoterAI		0.017	Neutral
Varity_R		0.47
gMVP		0.72
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs104894175; hg19: chr10-103991800;