Genetic Variant NM_002653.5:c.*57_*62delGCGCGG (chr5-135028716-TCCGCGC-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_002653.5(PITX1):c.*57_*62delGCGCGG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 1,245,734 control chromosomes in the GnomAD database, including 110,322 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.49 ( 20166 hom., cov: 0)

Exomes 𝑓: 0.40 ( 90156 hom. )

Consequence

PITX1
NM_002653.5 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.58

Publications

2 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 -10 ACMG points.

BP6

Variant 5-135028716-TCCGCGC-T is Benign according to our data. Variant chr5-135028716-TCCGCGC-T is described in ClinVar as [Benign]. Clinvar id is 1261620.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5 link	c.57_62delGCGCGG	3_prime_UTR_variant	Exon 3 of 3	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.57_62delGCGCGG	3_prime_UTR_variant	Exon 4 of 4		XP_047273274.1
PITX1	XM_047417319.1 link	c.57_62delGCGCGG	3_prime_UTR_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.57_62delGCGCGG		3_prime_UTR_variant	Exon 3 of 3	1	NM_002653.5	ENSP00000265340.6		P78337
PITX1	ENST00000506438.5 link	c.57_62delGCGCGG		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000427542.1		P78337

Frequencies

GnomAD3 genomes

AF:

0.490

AC:

73237

AN:

149584

Hom.:

20101

Cov.:

show subpopulations

Gnomad AFR

AF:

0.745

Gnomad AMI

AF:

0.377

Gnomad AMR

AF:

0.505

Gnomad ASJ

AF:

0.304

Gnomad EAS

AF:

0.468

Gnomad SAS

AF:

0.462

Gnomad FIN

AF:

0.326

Gnomad MID

AF:

0.284

Gnomad NFE

AF:

0.372

Gnomad OTH

AF:

0.455

GnomAD4 exome

AF:

0.400

AC:

438506

AN:

1096048

Hom.:

90156

AF XY:

0.402

AC XY:

212107

AN XY:

527978

show subpopulations

African (AFR)

AF:

0.761

AC:

16665

AN:

21890

American (AMR)

AF:

0.560

AC:

5117

AN:

9144

Ashkenazi Jewish (ASJ)

AF:

0.327

AC:

4536

AN:

13876

East Asian (EAS)

AF:

0.583

AC:

15237

AN:

26144

South Asian (SAS)

AF:

0.495

AC:

18057

AN:

36514

European-Finnish (FIN)

AF:

0.363

AC:

9665

AN:

26590

Middle Eastern (MID)

AF:

0.352

AC:

1055

AN:

3000

European-Non Finnish (NFE)

AF:

0.382

AC:

349286

AN:

914358

Other (OTH)

AF:

0.424

AC:

18888

AN:

44532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

10822

21644

32466

43288

54110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.490

AC:

73366

AN:

149686

Hom.:

20166

Cov.:

AF XY:

0.485

AC XY:

35426

AN XY:

73046

show subpopulations

African (AFR)

AF:

0.746

AC:

30486

AN:

40876

American (AMR)

AF:

0.506

AC:

7641

AN:

15090

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

1048

AN:

3446

East Asian (EAS)

AF:

0.467

AC:

2343

AN:

5012

South Asian (SAS)

AF:

0.463

AC:

2202

AN:

4760

European-Finnish (FIN)

AF:

0.326

AC:

3246

AN:

9964

Middle Eastern (MID)

AF:

0.288

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.372

AC:

25028

AN:

67278

Other (OTH)

AF:

0.458

AC:

953

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1557

3113

4670

6226

7783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.246

Hom.:

524

Bravo

AF:

0.512

Asia WGS

AF:

0.515

AC:

1769

AN:

3442

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 14, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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NM_002653.5:c.57_62delGCGCGG

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