Genetic Variant PITX1:p.Gly7Ala (chr5-135033862-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002653.5(PITX1):c.20G>C(p.Gly7Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000226 in 1,329,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G7V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

PITX1
NM_002653.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.97

Publications

0 publications found

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]

PITX1 links:

PITX1-AS1 (HGNC:48332): (PITX1 antisense RNA 1)

PITX1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33730683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5 link	c.20G>C	p.Gly7Ala	missense_variant	Exon 1 of 3	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.122G>C	p.Gly41Ala	missense_variant	Exon 2 of 4		XP_047273274.1
PITX1-AS1	NR_161235.1 link	n.267+322C>G		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12 link	c.20G>C	p.Gly7Ala	missense_variant	Exon 1 of 3	1	NM_002653.5	ENSP00000265340.6		P78337

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000226

AC:

AN:

1329174

Hom.:

Cov.:

AF XY:

0.00000305

AC XY:

AN XY:

655782

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26526

American (AMR)

AF:

0.00

AC:

AN:

26864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22140

East Asian (EAS)

AF:

0.00

AC:

AN:

31140

South Asian (SAS)

AF:

0.00

AC:

AN:

72232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3844

European-Non Finnish (NFE)

AF:

0.00000284

AC:

AN:

1057558

Other (OTH)

AF:

0.00

AC:

AN:

55042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.28

T;T;.;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.69

.;T;T;T

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.34

T;T;T;T

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.8

L;L;.;.

PhyloP100

5.0

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.97

N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.50

T;T;T;T

Sift4G

Benign

1.0

T;T;.;T

Polyphen

0.0

B;B;.;.

Vest4

0.27

MutPred

0.36

Loss of ubiquitination at K5 (P = 0.0605);Loss of ubiquitination at K5 (P = 0.0605);Loss of ubiquitination at K5 (P = 0.0605);Loss of ubiquitination at K5 (P = 0.0605);

MVP

0.76

MPC

2.1

ClinPred

0.63

GERP RS

2.8

PromoterAI

0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.15

gMVP

0.40

Mutation Taster

=88/12

polymorphism

(source)

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

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5-135033862-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over