Genetic Variant PITX1:p.Met27Val (chr5-135033803-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002653.5(PITX1):c.79A>G(p.Met27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,416,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 0.0000028 ( 0 hom. )

Consequence

PITX1
NM_002653.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.32

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23842621).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5 link	c.79A>G	p.Met27Val	missense_variant	Exon 1 of 3	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.181A>G	p.Met61Val	missense_variant	Exon 2 of 4		XP_047273274.1
PITX1-AS1	NR_161235.1 link	n.267+263T>C		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12 link	c.79A>G	p.Met27Val	missense_variant	Exon 1 of 3	1	NM_002653.5	ENSP00000265340.6		P78337

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000282

AC:

AN:

1416452

Hom.:

Cov.:

AF XY:

0.00000426

AC XY:

AN XY:

703732

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29932

American (AMR)

AF:

0.00

AC:

AN:

41328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25026

East Asian (EAS)

AF:

0.00

AC:

AN:

36640

South Asian (SAS)

AF:

0.00

AC:

AN:

82594

European-Finnish (FIN)

AF:

0.0000250

AC:

AN:

39976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4148

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1098164

Other (OTH)

AF:

0.00

AC:

AN:

58644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.79A>G (p.M27V) alteration is located in exon 1 (coding exon 1) of the PITX1 gene. This alteration results from a A to G substitution at nucleotide position 79, causing the methionine (M) at amino acid position 27 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.18

T;T;.;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.64

.;T;T;T

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.8

L;L;.;.

PhyloP100

3.3

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.72

N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.087

T;T;T;T

Sift4G

Benign

0.50

T;T;.;T

Polyphen

0.0

B;B;.;.

Vest4

0.11

MutPred

0.19

Loss of catalytic residue at M27 (P = 0.1047);Loss of catalytic residue at M27 (P = 0.1047);Loss of catalytic residue at M27 (P = 0.1047);Loss of catalytic residue at M27 (P = 0.1047);

MVP

0.94

MPC

1.0

ClinPred

0.35

GERP RS

1.3

PromoterAI

0.033

Neutral

(source)

Varity_R

0.25

gMVP

0.20

Mutation Taster

=92/8

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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5-135033803-T-C

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