5-135030100-A-T

Variant names:

• chr5-135030100-A-T
• rs888685
• NM_002653.5:c.403-779T>A

Variant summary

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

The NM_002653.5(PITX1):​c.403-779T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 152,004 control chromosomes in the GnomAD database, including 20,631 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 (20631 hom., cov: 32)
• Consequence: PITX1 NM_002653.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 4 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.72).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.741 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002653.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX1	NM_002653.5	MANE Select	c.403-779T>A		intron	N/A	NP_002644.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX1	ENST00000265340.12	TSL:1 MANE Select	c.403-779T>A		intron	N/A	ENSP00000265340.6	P78337
	PITX1	ENST00000506438.5	TSL:1	c.403-779T>A		intron	N/A	ENSP00000427542.1	P78337
	PITX1	ENST00000503586.1	TSL:3	n.525-779T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74586 AN: 151888 Hom.: 20565 Cov.: 32

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.492 AC: 74720 AN: 152004 Hom.: 20631 Cov.: 32 AF XY: 0.487 AC XY: 36156 AN XY: 74272

African (AFR) AF: 0.748 AC: 31005 AN: 41446

American (AMR) AF: 0.508 AC: 7767 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1049 AN: 3464

East Asian (EAS) AF: 0.474 AC: 2453 AN: 5172

South Asian (SAS) AF: 0.465 AC: 2245 AN: 4824

European-Finnish (FIN) AF: 0.327 AC: 3437 AN: 10524

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.373 AC: 25365 AN: 67968

Other (OTH) AF: 0.457 AC: 964 AN: 2110

Alfa AF: 0.444 Hom.: 2090

Bravo AF: 0.515

Asia WGS AF: 0.524 AC: 1820 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.90
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: rs888685; hg19: chr5-134365790;