Genetic Variant PITX1:c.169+1003A>G (chr5-135032710-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002653.5(PITX1):c.169+1003A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 216,218 control chromosomes in the GnomAD database, including 5,116 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 4602 hom., cov: 33)

Exomes 𝑓: 0.11 ( 514 hom. )

Consequence

PITX1
NM_002653.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0250

Publications

1 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 Gene-Disease associations (from GenCC):

clubfoot
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
brachydactyly-elbow wrist dysplasia syndrome
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

PITX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5 link	c.169+1003A>G	intron_variant	Intron 1 of 2	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.271+1003A>G	intron_variant	Intron 2 of 3		XP_047273274.1
PITX1	XM_047417319.1 link	c.-177+728A>G	intron_variant	Intron 1 of 2		XP_047273275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12 link	c.169+1003A>G		intron_variant	Intron 1 of 2	1	NM_002653.5	ENSP00000265340.6		P78337

Frequencies

GnomAD3 genomes

AF:

0.199

AC:

30237

AN:

152104

Hom.:

4567

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.206

Gnomad ASJ

AF:

0.0672

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0501

Gnomad FIN

AF:

0.0755

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.191

GnomAD4 exome

AF:

0.107

AC:

6847

AN:

63996

Hom.:

514

AF XY:

0.101

AC XY:

3509

AN XY:

34750

show subpopulations

African (AFR)

AF:

0.445

AC:

237

AN:

532

American (AMR)

AF:

0.195

AC:

422

AN:

2162

Ashkenazi Jewish (ASJ)

AF:

0.0731

AC:

AN:

1314

East Asian (EAS)

AF:

0.00

AC:

AN:

1688

South Asian (SAS)

AF:

0.0543

AC:

705

AN:

12988

European-Finnish (FIN)

AF:

0.0883

AC:

398

AN:

4508

Middle Eastern (MID)

AF:

0.0654

AC:

AN:

734

European-Non Finnish (NFE)

AF:

0.124

AC:

4583

AN:

36826

Other (OTH)

AF:

0.110

AC:

358

AN:

3244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.534

Heterozygous variant carriers

285

570

854

1139

1424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.199

AC:

30345

AN:

152222

Hom.:

4602

Cov.:

AF XY:

0.192

AC XY:

14301

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.424

AC:

17579

AN:

41482

American (AMR)

AF:

0.207

AC:

3162

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0672

AC:

233

AN:

3466

East Asian (EAS)

AF:

0.00173

AC:

AN:

5194

South Asian (SAS)

AF:

0.0513

AC:

248

AN:

4830

European-Finnish (FIN)

AF:

0.0755

AC:

801

AN:

10610

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.116

AC:

7866

AN:

68020

Other (OTH)

AF:

0.189

AC:

400

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1102

2204

3305

4407

5509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

284

568

852

1136

1420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0696

Hom.:

130

Bravo

AF:

0.221

Asia WGS

AF:

0.0520

AC:

182

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.025

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over