5-135028828-C-G

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.896G>C(p.Gly299Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,611,896 control chromosomes in the GnomAD database, including 61,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5044 hom., cov: 33)

Exomes 𝑓: 0.27 ( 56215 hom. )

Consequence

PITX1
NM_002653.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.54

Publications

34 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 (MetaRNN=0.00277856).

BP6

Variant 5-135028828-C-G is Benign according to our data. Variant chr5-135028828-C-G is described in ClinVar as [Benign]. Clinvar id is 286868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5 link	c.896G>C	p.Gly299Ala	missense_variant	Exon 3 of 3	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.998G>C	p.Gly333Ala	missense_variant	Exon 4 of 4		XP_047273274.1
PITX1	XM_047417319.1 link	c.551G>C	p.Gly184Ala	missense_variant	Exon 3 of 3		XP_047273275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12 link	c.896G>C	p.Gly299Ala	missense_variant	Exon 3 of 3	1	NM_002653.5	ENSP00000265340.6		P78337
PITX1	ENST00000506438.5 link	c.896G>C	p.Gly299Ala	missense_variant	Exon 4 of 4	1		ENSP00000427542.1		P78337

Frequencies

GnomAD3 genomes

AF:

0.244

AC:

36998

AN:

151880

Hom.:

5044

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.357

Gnomad AMR

AF:

0.283

Gnomad ASJ

AF:

0.236

Gnomad EAS

AF:

0.471

Gnomad SAS

AF:

0.414

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.201

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.229

GnomAD2 exomes

AF:

0.292

AC:

71893

AN:

246276

AF XY:

0.295

show subpopulations

Gnomad AFR exome

AF:

0.151

Gnomad AMR exome

AF:

0.345

Gnomad ASJ exome

AF:

0.247

Gnomad EAS exome

AF:

0.467

Gnomad FIN exome

AF:

0.259

Gnomad NFE exome

AF:

0.253

Gnomad OTH exome

AF:

0.276

GnomAD4 exome

AF:

0.270

AC:

393595

AN:

1459906

Hom.:

56215

Cov.:

AF XY:

0.273

AC XY:

198473

AN XY:

726260

show subpopulations

African (AFR)

AF:

0.158

AC:

5277

AN:

33452

American (AMR)

AF:

0.338

AC:

15061

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.242

AC:

6319

AN:

26104

East Asian (EAS)

AF:

0.543

AC:

21544

AN:

39650

South Asian (SAS)

AF:

0.385

AC:

33175

AN:

86202

European-Finnish (FIN)

AF:

0.257

AC:

13556

AN:

52720

Middle Eastern (MID)

AF:

0.255

AC:

1410

AN:

5528

European-Non Finnish (NFE)

AF:

0.253

AC:

280770

AN:

1111372

Other (OTH)

AF:

0.274

AC:

16483

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

16688

33375

50063

66750

83438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.243

AC:

37002

AN:

151990

Hom.:

5044

Cov.:

AF XY:

0.247

AC XY:

18356

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.157

AC:

6527

AN:

41522

American (AMR)

AF:

0.282

AC:

4318

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

817

AN:

3466

East Asian (EAS)

AF:

0.471

AC:

2409

AN:

5118

South Asian (SAS)

AF:

0.414

AC:

1997

AN:

4828

European-Finnish (FIN)

AF:

0.251

AC:

2651

AN:

10548

Middle Eastern (MID)

AF:

0.202

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.256

AC:

17407

AN:

67898

Other (OTH)

AF:

0.233

AC:

492

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1415

2830

4244

5659

7074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.223

Hom.:

1333

Bravo

AF:

0.239

ESP6500AA

AF:

0.155

AC:

685

ESP6500EA

AF:

0.248

AC:

2132

ExAC

AF:

0.285

AC:

34590

EpiCase

AF:

0.258

EpiControl

AF:

0.250

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 23, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clubfoot

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brachydactyly-elbow wrist dysplasia syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 02, 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

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.071

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

.;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.045

N;N

PhyloP100

7.5

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.98

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.75

T;T

Sift4G

Benign

0.77

T;T

Polyphen

0.15

B;B

Vest4

0.076

MPC

1.1

ClinPred

0.030

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.10

gMVP

0.42

Mutation Taster

=94/6

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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5-135028828-C-G

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