NM_002653.5:c.418C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002653.5(PITX1):c.418C>A(p.Arg140Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.127 in 1,597,336 control chromosomes in the GnomAD database, including 17,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 4603 hom., cov: 34)

Exomes 𝑓: 0.12 ( 12805 hom. )

Consequence

PITX1
NM_002653.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.58

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 5-135029306-G-T is Benign according to our data. Variant chr5-135029306-G-T is described in ClinVar as Benign. ClinVar VariationId is 285760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5 link	c.418C>A	p.Arg140Arg	synonymous_variant	Exon 3 of 3	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.520C>A	p.Arg174Arg	synonymous_variant	Exon 4 of 4		XP_047273274.1
PITX1	XM_047417319.1 link	c.73C>A	p.Arg25Arg	synonymous_variant	Exon 3 of 3		XP_047273275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PITX1	ENST00000265340.12 link	c.418C>A	p.Arg140Arg	synonymous_variant	Exon 3 of 3	1	NM_002653.5	ENSP00000265340.6	P78337
PITX1	ENST00000506438.5 link	c.418C>A	p.Arg140Arg	synonymous_variant	Exon 4 of 4	1		ENSP00000427542.1	P78337
PITX1	ENST00000503586.1 link	n.540C>A		non_coding_transcript_exon_variant	Exon 3 of 3	3
PITX1	ENST00000504936.1 link	n.751C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.199

AC:

30230

AN:

152092

Hom.:

4568

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.205

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

GnomAD2 exomes

AF:

0.123

AC:

28929

AN:

235206

AF XY:

0.113

show subpopulations

Gnomad AFR exome

AF:

0.433

Gnomad AMR exome

AF:

0.193

Gnomad ASJ exome

AF:

0.0665

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.0807

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.122

GnomAD4 exome

AF:

0.119

AC:

172354

AN:

1445126

Hom.:

12805

Cov.:

AF XY:

0.116

AC XY:

83050

AN XY:

716832

show subpopulations

African (AFR)

AF:

0.427

AC:

14099

AN:

33026

American (AMR)

AF:

0.196

AC:

8573

AN:

43704

Ashkenazi Jewish (ASJ)

AF:

0.0670

AC:

1667

AN:

24888

East Asian (EAS)

AF:

0.000152

AC:

AN:

39518

South Asian (SAS)

AF:

0.0492

AC:

4102

AN:

83344

European-Finnish (FIN)

AF:

0.0812

AC:

4258

AN:

52438

Middle Eastern (MID)

AF:

0.0705

AC:

401

AN:

5686

European-Non Finnish (NFE)

AF:

0.120

AC:

131827

AN:

1102870

Other (OTH)

AF:

0.124

AC:

7421

AN:

59652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

7314

14628

21943

29257

36571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4994

9988

14982

19976

24970

<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:

30338

AN:

152210

Hom.:

4603

Cov.:

AF XY:

0.192

AC XY:

14301

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.424

AC:

17574

AN:

41488

American (AMR)

AF:

0.207

AC:

3161

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0671

AC:

233

AN:

3470

East Asian (EAS)

AF:

0.00174

AC:

AN:

5178

South Asian (SAS)

AF:

0.0512

AC:

247

AN:

4828

European-Finnish (FIN)

AF:

0.0755

AC:

802

AN:

10618

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.116

AC:

7866

AN:

68012

Other (OTH)

AF:

0.189

AC:

400

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1143

2285

3428

4570

5713

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:

0.146

Hom.:

3297

Bravo

AF:

0.221

Asia WGS

AF:

0.0520

AC:

182

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 08, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Oct 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

6.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over