Genetic Variant PITX1:p.Arg40His (chr5-135033763-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002653.5(PITX1):c.119G>A(p.Arg40His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,437,596 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. R40L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PITX1
NM_002653.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.27

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5 link	c.119G>A	p.Arg40His	missense_variant	Exon 1 of 3	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.221G>A	p.Arg74His	missense_variant	Exon 2 of 4		XP_047273274.1
PITX1-AS1	NR_161235.1 link	n.267+223C>T		intron_variant	Intron 1 of 5
PITX1	XM_047417319.1 link	c.-502G>A		upstream_gene_variant			XP_047273275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12 link	c.119G>A	p.Arg40His	missense_variant	Exon 1 of 3	1	NM_002653.5	ENSP00000265340.6		P78337

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000481

AC:

AN:

207896

AF XY:

0.00000857

show subpopulations

Gnomad AFR exome

AF:

0.0000940

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:

0.00000209

AC:

AN:

1437596

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

715288

show subpopulations

African (AFR)

AF:

0.0000943

AC:

AN:

31804

American (AMR)

AF:

0.00

AC:

AN:

44090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25714

East Asian (EAS)

AF:

0.00

AC:

AN:

38660

South Asian (SAS)

AF:

0.00

AC:

AN:

84852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4682

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106956

Other (OTH)

AF:

0.00

AC:

AN:

59530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000878

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T;.;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

.;T;T;T

M_CAP

Pathogenic

0.92

MetaRNN

Uncertain

0.59

D;D;D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

2.0

M;M;.;.

PhyloP100

7.3

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.81

N;N;N;N

REVEL

Uncertain

0.51

Sift

Benign

0.090

T;T;T;T

Sift4G

Benign

0.21

T;T;.;T

Polyphen

1.0

D;D;.;.

Vest4

0.34

MutPred

0.19

Loss of glycosylation at P42 (P = 0.2742);Loss of glycosylation at P42 (P = 0.2742);Loss of glycosylation at P42 (P = 0.2742);Loss of glycosylation at P42 (P = 0.2742);

MVP

0.91

MPC

2.3

ClinPred

0.79

GERP RS

4.2

PromoterAI

0.0014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.20

Mutation Taster

=69/31

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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chr5-135033763-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