10-102231624-G-A

Variant names:

• chr10-102231624-G-A
• rs2281983
• NM_005029.4:c.285C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005029.4(PITX3):​c.285C>T​(p.Ile95Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 1,608,126 control chromosomes in the GnomAD database, including 315,660 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I95I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.65 (32878 hom., cov: 32)
  • Exomes 𝑓: 0.62 (282782 hom.)
• Consequence: PITX3 NM_005029.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.215
• Publications: 42 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 10-102231624-G-A is Benign according to our data. Variant chr10-102231624-G-A is described in ClinVar as Benign. ClinVar VariationId is 196404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.215 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

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.285C>T	p.Ile95Ile	synonymous	Exon 3 of 4	NP_005020.1	O75364
	GBF1	NM_001391923.1		c.-11+708G>A		intron	N/A	NP_001378852.1	Q92538-2
	GBF1	NM_001391924.1		c.-149+708G>A		intron	N/A	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.285C>T	p.Ile95Ile	synonymous	Exon 3 of 4	ENSP00000359019.3	O75364

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99367 AN: 151924 Hom.: 32833 Cov.: 32

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.627

GnomAD2 exomes AF: 0.617 AC: 148912 AN: 241510 AF XY: 0.609

Gnomad AFR exome AF: 0.749

Gnomad AMR exome AF: 0.581

Gnomad ASJ exome AF: 0.571

Gnomad EAS exome AF: 0.772

Gnomad FIN exome AF: 0.617

Gnomad NFE exome AF: 0.615

Gnomad OTH exome AF: 0.608

GnomAD4 exome AF: 0.621 AC: 904366 AN: 1456084 Hom.: 282782 Cov.: 41 AF XY: 0.617 AC XY: 447061 AN XY: 724204

African (AFR) AF: 0.753 AC: 25147 AN: 33406

American (AMR) AF: 0.588 AC: 25909 AN: 44066

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 14953 AN: 26012

East Asian (EAS) AF: 0.735 AC: 29080 AN: 39548

South Asian (SAS) AF: 0.512 AC: 43829 AN: 85600

European-Finnish (FIN) AF: 0.614 AC: 32501 AN: 52914

Middle Eastern (MID) AF: 0.551 AC: 3114 AN: 5648

European-Non Finnish (NFE) AF: 0.624 AC: 692303 AN: 1108746

Other (OTH) AF: 0.624 AC: 37530 AN: 60144

GnomAD4 genome AF: 0.654 AC: 99470 AN: 152042 Hom.: 32878 Cov.: 32 AF XY: 0.651 AC XY: 48406 AN XY: 74346

African (AFR) AF: 0.750 AC: 31135 AN: 41510

American (AMR) AF: 0.612 AC: 9357 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2044 AN: 3470

East Asian (EAS) AF: 0.747 AC: 3839 AN: 5138

South Asian (SAS) AF: 0.515 AC: 2487 AN: 4828

European-Finnish (FIN) AF: 0.618 AC: 6533 AN: 10576

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42034 AN: 67910

Other (OTH) AF: 0.632 AC: 1335 AN: 2112

Alfa AF: 0.612 Hom.: 12964

Bravo AF: 0.659

Asia WGS AF: 0.637 AC: 2214 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Anterior segment dysgenesis 1 (1)
-	-	1	Cataract 11 multiple types (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		-0.21
PromoterAI		-0.054	Neutral
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2281983; hg19: chr10-103991381; COSMIC: COSV64174922; COSMIC: COSV64174922;