10-102238914-A-T

Variant names:

• chr10-102238914-A-T
• rs4919621
• NM_005029.4:c.-13+2419T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005029.4(PITX3):​c.-13+2419T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 152,026 control chromosomes in the GnomAD database, including 33,417 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.66 (33417 hom., cov: 31)
• Consequence: PITX3 NM_005029.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00300
• Publications: 24 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX3	NM_005029.4	c.-13+2419T>A		intron_variant	Intron 1 of 3	ENST00000370002.8	NP_005020.1
GBF1	NM_001391923.1	c.-11+7998A>T		intron_variant	Intron 1 of 39		NP_001378852.1
GBF1	NM_001391924.1	c.-148-6730A>T		intron_variant	Intron 1 of 40		NP_001378853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX3	ENST00000370002.8	c.-13+2419T>A		intron_variant	Intron 1 of 3	1	NM_005029.4	ENSP00000359019.3

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100111 AN: 151908 Hom.: 33362 Cov.: 31

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.630

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.659 AC: 100225 AN: 152026 Hom.: 33417 Cov.: 31 AF XY: 0.656 AC XY: 48728 AN XY: 74288

African (AFR) AF: 0.764 AC: 31681 AN: 41462

American (AMR) AF: 0.614 AC: 9387 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2045 AN: 3472

East Asian (EAS) AF: 0.749 AC: 3875 AN: 5176

South Asian (SAS) AF: 0.519 AC: 2499 AN: 4814

European-Finnish (FIN) AF: 0.619 AC: 6517 AN: 10532

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.620 AC: 42171 AN: 67974

Other (OTH) AF: 0.635 AC: 1340 AN: 2110

Alfa AF: 0.648 Hom.: 3979

Bravo AF: 0.664

Asia WGS AF: 0.640 AC: 2225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		0.0030
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4919621; hg19: chr10-103998671;