5-135033813-T-TGGC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PM4_SupportingBS2

The NM_002653.5(PITX1):c.66_68dupGCC(p.Pro23dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000457 in 1,553,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

PITX1
NM_002653.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.71

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 -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_002653.5. Strenght limited to Supporting due to length of the change: 1aa.

BS2

High AC in GnomAdExome4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5 link	c.66_68dupGCC	p.Pro23dup	disruptive_inframe_insertion	Exon 1 of 3	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.168_170dupGCC	p.Pro57dup	disruptive_inframe_insertion	Exon 2 of 4		XP_047273274.1
PITX1-AS1	NR_161235.1 link	n.267+286_267+288dupGGC		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12 link	c.66_68dupGCC	p.Pro23dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_002653.5	ENSP00000265340.6		P78337

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000506

AC:

AN:

158042

AF XY:

0.0000559

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:

0.0000142

Gnomad OTH exome

AF:

0.000250

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1402382

Hom.:

Cov.:

AF XY:

0.0000575

AC XY:

AN XY:

695838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29406

American (AMR)

AF:

0.00

AC:

AN:

39066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24726

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35600

South Asian (SAS)

AF:

0.000234

AC:

AN:

81098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4064

European-Non Finnish (NFE)

AF:

0.0000440

AC:

AN:

1091636

Other (OTH)

AF:

0.0000344

AC:

AN:

58184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151168

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73764

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41140

American (AMR)

AF:

0.0000656

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5110

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10494

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67622

Other (OTH)

AF:

0.00

AC:

AN:

2082

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PITX1-related disorder

Uncertain:1

Feb 28, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PITX1 c.66_68dupGCC variant is predicted to result in an in-frame duplication (p.Pro24dup). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.025% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-134369503-T-TGGC). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.66_68dup, results in the insertion of 1 amino acid(s) of the PITX1 protein (p.Pro24dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs776272532, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PITX1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.7

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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5-135033813-T-TGGC

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