dbSNP rs6872664: PITX1:c.170-400G>A (chr5-135031908-C-T) – 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.170-400G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 229,816 control chromosomes in the GnomAD database, including 5,215 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 ( 4603 hom., cov: 33)

Exomes 𝑓: 0.10 ( 612 hom. )

Consequence

PITX1
NM_002653.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.443

Publications

6 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=-0.91).

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.170-400G>A	intron_variant	Intron 1 of 2	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.272-400G>A	intron_variant	Intron 2 of 3		XP_047273274.1
PITX1	XM_047417319.1 link	c.-176-400G>A	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.170-400G>A		intron_variant	Intron 1 of 2	1	NM_002653.5	ENSP00000265340.6		P78337

Frequencies

GnomAD3 genomes

AF:

0.199

AC:

30225

AN:

152060

Hom.:

4568

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.206

Gnomad ASJ

AF:

0.0671

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0499

Gnomad FIN

AF:

0.0755

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.191

GnomAD4 exome

AF:

0.100

AC:

7775

AN:

77638

Hom.:

612

Cov.:

AF XY:

0.0964

AC XY:

3859

AN XY:

40012

show subpopulations

African (AFR)

AF:

0.369

AC:

721

AN:

1956

American (AMR)

AF:

0.191

AC:

791

AN:

4136

Ashkenazi Jewish (ASJ)

AF:

0.0671

AC:

135

AN:

2012

East Asian (EAS)

AF:

0.00

AC:

AN:

4044

South Asian (SAS)

AF:

0.0435

AC:

363

AN:

8346

European-Finnish (FIN)

AF:

0.0766

AC:

267

AN:

3486

Middle Eastern (MID)

AF:

0.0701

AC:

AN:

328

European-Non Finnish (NFE)

AF:

0.102

AC:

5010

AN:

48916

Other (OTH)

AF:

0.105

AC:

465

AN:

4414

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

320

641

961

1282

1602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

30333

AN:

152178

Hom.:

4603

Cov.:

AF XY:

0.192

AC XY:

14295

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.424

AC:

17565

AN:

41448

American (AMR)

AF:

0.207

AC:

3163

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0671

AC:

233

AN:

3470

East Asian (EAS)

AF:

0.00174

AC:

AN:

5186

South Asian (SAS)

AF:

0.0511

AC:

247

AN:

4830

European-Finnish (FIN)

AF:

0.0755

AC:

801

AN:

10614

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.116

AC:

7869

AN:

68016

Other (OTH)

AF:

0.189

AC:

399

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1109

2219

3328

4438

5547

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:

0.172

Hom.:

455

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

-0.91

CADD

Benign

(source)

DANN

Benign

0.53

PhyloP100

0.44

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