5-135032710-T-C

Variant names:

• chr5-135032710-T-C
• rs7700313
• NM_002653.5:c.169+1003A>G

Variant summary

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

The NM_002653.5(PITX1):​c.169+1003A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 216,218 control chromosomes in the GnomAD database, including 5,116 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 0.20 (4602 hom., cov: 33)
  • Exomes 𝑓: 0.11 (514 hom.)
• Consequence: PITX1 NM_002653.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250
• Publications: 1 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=-0.5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.419 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.169+1003A>G		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.169+1003A>G		intron	N/A	ENSP00000265340.6	P78337
	PITX1	ENST00000506438.5	TSL:1	c.169+1003A>G		intron	N/A	ENSP00000427542.1	P78337
	PITX1	ENST00000507253.5	TSL:3	c.169+1003A>G		intron	N/A	ENSP00000422908.1	D6R9U1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30237 AN: 152104 Hom.: 4567 Cov.: 33

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.0672

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0501

Gnomad FIN AF: 0.0755

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.107 AC: 6847 AN: 63996 Hom.: 514 AF XY: 0.101 AC XY: 3509 AN XY: 34750

African (AFR) AF: 0.445 AC: 237 AN: 532

American (AMR) AF: 0.195 AC: 422 AN: 2162

Ashkenazi Jewish (ASJ) AF: 0.0731 AC: 96 AN: 1314

East Asian (EAS) AF: 0.00 AC: 0 AN: 1688

South Asian (SAS) AF: 0.0543 AC: 705 AN: 12988

European-Finnish (FIN) AF: 0.0883 AC: 398 AN: 4508

Middle Eastern (MID) AF: 0.0654 AC: 48 AN: 734

European-Non Finnish (NFE) AF: 0.124 AC: 4583 AN: 36826

Other (OTH) AF: 0.110 AC: 358 AN: 3244

GnomAD4 genome AF: 0.199 AC: 30345 AN: 152222 Hom.: 4602 Cov.: 33 AF XY: 0.192 AC XY: 14301 AN XY: 74444

African (AFR) AF: 0.424 AC: 17579 AN: 41482

American (AMR) AF: 0.207 AC: 3162 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 233 AN: 3466

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5194

South Asian (SAS) AF: 0.0513 AC: 248 AN: 4830

European-Finnish (FIN) AF: 0.0755 AC: 801 AN: 10610

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7866 AN: 68020

Other (OTH) AF: 0.189 AC: 400 AN: 2116

Alfa AF: 0.0696 Hom.: 130

Bravo AF: 0.221

Asia WGS AF: 0.0520 AC: 182 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.88
PhyloP100		0.025
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: rs7700313; hg19: chr5-134368400;