rs3805663

Variant names:

• chr5-135030510-A-G
• rs3805663
• NM_002653.5:c.402+766T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002653.5(PITX1):​c.402+766T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,092 control chromosomes in the GnomAD database, including 20,630 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 0.49 (20630 hom., cov: 33)
• Consequence: PITX1 NM_002653.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.698
• Publications: 24 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 -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 = 0.741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5	c.402+766T>C		intron_variant	Intron 2 of 2	ENST00000265340.12	NP_002644.4
PITX1	XM_047417318.1	c.504+766T>C		intron_variant	Intron 3 of 3		XP_047273274.1
PITX1	XM_047417319.1	c.57+766T>C		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.402+766T>C		intron_variant	Intron 2 of 2	1	NM_002653.5	ENSP00000265340.6
PITX1	ENST00000506438.5	c.402+766T>C		intron_variant	Intron 3 of 3	1		ENSP00000427542.1
PITX1	ENST00000503586.1	n.524+766T>C		intron_variant	Intron 2 of 2	3
PITX1	ENST00000504936.1	n.735+766T>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74595 AN: 151974 Hom.: 20563 Cov.: 33

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.454

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.491 AC: 74731 AN: 152092 Hom.: 20630 Cov.: 33 AF XY: 0.487 AC XY: 36176 AN XY: 74358

African (AFR) AF: 0.748 AC: 31023 AN: 41498

American (AMR) AF: 0.508 AC: 7757 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1048 AN: 3466

East Asian (EAS) AF: 0.473 AC: 2449 AN: 5176

South Asian (SAS) AF: 0.466 AC: 2244 AN: 4812

European-Finnish (FIN) AF: 0.327 AC: 3457 AN: 10570

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.373 AC: 25358 AN: 67974

Other (OTH) AF: 0.455 AC: 961 AN: 2110

Alfa AF: 0.423 Hom.: 32658

Bravo AF: 0.514

Asia WGS AF: 0.524 AC: 1820 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	12
DANN	Benign	0.40
PhyloP100		0.70
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: rs3805663; hg19: chr5-134366200;