Genetic Variant PITX1:p.Ala47Ser (chr5-135033743-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_002653.5(PITX1):c.139G>T(p.Ala47Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,443,678 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

PITX1
NM_002653.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.18

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18234721).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5 link	c.139G>T	p.Ala47Ser	missense_variant	Exon 1 of 3	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.241G>T	p.Ala81Ser	missense_variant	Exon 2 of 4		XP_047273274.1
PITX1-AS1	NR_161235.1 link	n.267+203C>A		intron_variant	Intron 1 of 5
PITX1	XM_047417319.1 link	c.-482G>T		upstream_gene_variant			XP_047273275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12 link	c.139G>T	p.Ala47Ser	missense_variant	Exon 1 of 3	1	NM_002653.5	ENSP00000265340.6		P78337

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000461

AC:

AN:

217076

AF XY:

0.00

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:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1443678

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32664

American (AMR)

AF:

0.00

AC:

AN:

44464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25908

East Asian (EAS)

AF:

0.00

AC:

AN:

39266

South Asian (SAS)

AF:

0.00

AC:

AN:

85564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5008

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1109174

Other (OTH)

AF:

0.00

AC:

AN:

59776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000858

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 19, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.14

T;T;.;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

.;T;T;T

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Benign

0.90

L;L;.;.

PhyloP100

5.2

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.26

N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.81

T;T;T;T

Sift4G

Benign

0.75

T;T;.;T

Polyphen

0.0030

B;B;.;.

Vest4

0.15

MutPred

0.18

Gain of phosphorylation at A47 (P = 0.0024);Gain of phosphorylation at A47 (P = 0.0024);Gain of phosphorylation at A47 (P = 0.0024);Gain of phosphorylation at A47 (P = 0.0024);

MVP

0.73

MPC

0.96

ClinPred

0.45

GERP RS

3.3

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.15

gMVP

0.26

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr5-135033743-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over