chr10-102230754-G-A

Variant names:

• chr10-102230754-G-A
• rs1021921907
• NM_005029.4:c.669C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_005029.4(PITX3):​c.669C>T​(p.Pro223Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,331,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: PITX3 NM_005029.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 10-102230754-G-A is Benign according to our data. Variant chr10-102230754-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2968291.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.

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.669C>T	p.Pro223Pro	synonymous	Exon 4 of 4	NP_005020.1	O75364
	GBF1	NM_001391923.1		c.-173G>A		5_prime_UTR	Exon 1 of 40	NP_001378852.1	Q92538-2
	GBF1	NM_001391924.1		c.-311G>A		5_prime_UTR	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.669C>T	p.Pro223Pro	synonymous	Exon 4 of 4	ENSP00000359019.3	O75364

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.51e-7 AC: 1 AN: 1331392 Hom.: 0 Cov.: 32 AF XY: 0.00000153 AC XY: 1 AN XY: 654664

African (AFR) AF: 0.00 AC: 0 AN: 26758

American (AMR) AF: 0.00 AC: 0 AN: 24174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21340

East Asian (EAS) AF: 0.00 AC: 0 AN: 32180

South Asian (SAS) AF: 0.0000145 AC: 1 AN: 68832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1052394

Other (OTH) AF: 0.00 AC: 0 AN: 54916

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.2
DANN	Benign	0.95
PhyloP100		-1.6

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: rs1021921907; hg19: chr10-103990511;