NM_002653.5:c.748G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002653.5(PITX1):​c.748G>A​(p.Gly250Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PITX1
NM_002653.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.31
Variant links:
Genes affected
PITX1 (HGNC:9004): (paired like homeodomain 1) This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family are involved in organ development and left-right asymmetry. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13963202).
BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PITX1NM_002653.5 linkc.748G>A p.Gly250Ser missense_variant Exon 3 of 3 ENST00000265340.12 NP_002644.4 P78337X5D9A5
PITX1XM_047417318.1 linkc.850G>A p.Gly284Ser missense_variant Exon 4 of 4 XP_047273274.1
PITX1XM_047417319.1 linkc.403G>A p.Gly135Ser missense_variant Exon 3 of 3 XP_047273275.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PITX1ENST00000265340.12 linkc.748G>A p.Gly250Ser missense_variant Exon 3 of 3 1 NM_002653.5 ENSP00000265340.6 P78337
PITX1ENST00000506438.5 linkc.748G>A p.Gly250Ser missense_variant Exon 4 of 4 1 ENSP00000427542.1 P78337

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251032
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461804
Hom.:
0
Cov.:
34
AF XY:
0.00000550
AC XY:
4
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 250 of the PITX1 protein (p.Gly250Ser). This variant is present in population databases (rs748803285, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PITX1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PITX1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.19
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.18
T;T
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.25
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.78
.;T
M_CAP
Uncertain
0.086
D
MetaRNN
Benign
0.14
T;T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
0.84
L;L
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-0.35
N;N
REVEL
Benign
0.27
Sift
Benign
0.48
T;T
Sift4G
Benign
0.63
T;T
Polyphen
0.12
B;B
Vest4
0.24
MutPred
0.23
Gain of phosphorylation at G250 (P = 0.0582);Gain of phosphorylation at G250 (P = 0.0582);
MVP
0.80
MPC
1.1
ClinPred
0.14
T
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.062
gMVP
0.51

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs748803285; hg19: chr5-134364666; API