Genetic Variant PITX1:p.Gly7Asp (chr5-135033862-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002653.5(PITX1):c.20G>A(p.Gly7Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000113 in 1,329,174 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000011 ( 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5 link	c.20G>A	p.Gly7Asp	missense_variant	Exon 1 of 3	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.122G>A	p.Gly41Asp	missense_variant	Exon 2 of 4		XP_047273274.1
PITX1-AS1	NR_161235.1 link	n.267+322C>T		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>A	p.Gly7Asp	missense_variant	Exon 1 of 3	1	NM_002653.5	ENSP00000265340.6		P78337

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

82874

AF XY:

0.0000210

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000113

AC:

AN:

1329174

Hom.:

Cov.:

AF XY:

0.0000122

AC XY:

AN XY:

655782

show subpopulations

African (AFR)

AF:

0.0000377

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:

0.0000692

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:

0.00000851

AC:

AN:

1057558

Other (OTH)

AF:

0.00

AC:

AN:

55042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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

Uncertain

0.35

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;T;.;T

Eigen

Benign

0.012

Eigen_PC

Benign

0.021

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.71

.;T;T;T

M_CAP

Pathogenic

0.95

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.8

L;L;.;.

PhyloP100

5.0

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Uncertain

0.49

Sift

Benign

0.032

D;D;D;D

Sift4G

Benign

0.29

T;T;.;T

Polyphen

0.67

P;P;.;.

Vest4

0.43

MutPred

0.33

Loss of MoRF binding (P = 0.0125);Loss of MoRF binding (P = 0.0125);Loss of MoRF binding (P = 0.0125);Loss of MoRF binding (P = 0.0125);

MVP

0.91

MPC

2.4

ClinPred

0.44

GERP RS

2.8

PromoterAI

0.042

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.20

gMVP

0.44

Mutation Taster

=84/16

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-T

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