NM_002653.5:c.403-80A>G

Variant names:

• chr5-135029401-T-C
• rs474853
• NM_002653.5:c.403-80A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002653.5(PITX1):​c.403-80A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,218,474 control chromosomes in the GnomAD database, including 105,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.49 (20641 hom., cov: 33)
  • Exomes 𝑓: 0.39 (85138 hom.)
• Consequence: PITX1 NM_002653.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13
• Publications: 9 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-135029401-T-C is Benign according to our data. Variant chr5-135029401-T-C is described in ClinVar as Benign. ClinVar VariationId is 1294906.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5	c.403-80A>G		intron_variant	Intron 2 of 2	ENST00000265340.12	NP_002644.4
PITX1	XM_047417318.1	c.505-80A>G		intron_variant	Intron 3 of 3		XP_047273274.1
PITX1	XM_047417319.1	c.58-80A>G		intron_variant	Intron 2 of 2		XP_047273275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12	c.403-80A>G		intron_variant	Intron 2 of 2	1	NM_002653.5	ENSP00000265340.6
PITX1	ENST00000506438.5	c.403-80A>G		intron_variant	Intron 3 of 3	1		ENSP00000427542.1
PITX1	ENST00000503586.1	n.525-80A>G		intron_variant	Intron 2 of 2	3
PITX1	ENST00000504936.1	n.736-80A>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74638 AN: 152036 Hom.: 20575 Cov.: 33

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.455

GnomAD4 exome AF: 0.391 AC: 416471 AN: 1066322 Hom.: 85138 AF XY: 0.391 AC XY: 208347 AN XY: 532916

African (AFR) AF: 0.746 AC: 17883 AN: 23958

American (AMR) AF: 0.538 AC: 15021 AN: 27936

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 5581 AN: 18030

East Asian (EAS) AF: 0.546 AC: 20385 AN: 37322

South Asian (SAS) AF: 0.437 AC: 27338 AN: 62610

European-Finnish (FIN) AF: 0.338 AC: 16216 AN: 48016

Middle Eastern (MID) AF: 0.335 AC: 1150 AN: 3432

European-Non Finnish (NFE) AF: 0.368 AC: 294258 AN: 798910

Other (OTH) AF: 0.404 AC: 18639 AN: 46108

GnomAD4 genome AF: 0.491 AC: 74772 AN: 152152 Hom.: 20641 Cov.: 33 AF XY: 0.486 AC XY: 36182 AN XY: 74380

African (AFR) AF: 0.748 AC: 31056 AN: 41540

American (AMR) AF: 0.508 AC: 7768 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1050 AN: 3472

East Asian (EAS) AF: 0.473 AC: 2439 AN: 5154

South Asian (SAS) AF: 0.466 AC: 2249 AN: 4822

European-Finnish (FIN) AF: 0.326 AC: 3457 AN: 10594

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.373 AC: 25354 AN: 67952

Other (OTH) AF: 0.457 AC: 966 AN: 2116

Alfa AF: 0.426 Hom.: 34519

Bravo AF: 0.515

Asia WGS AF: 0.524 AC: 1820 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.50
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs474853; hg19: chr5-134365091; COSMIC: COSV54761505; COSMIC: COSV54761505;