rs6596189

Variant names:

• chr5-135032479-C-T
• rs6596189
• NM_002653.5:c.170-971G>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.170-971G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 152,108 control chromosomes in the GnomAD database, including 4,598 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 (4598 hom., cov: 33)
• Consequence: PITX1 NM_002653.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.274
• Publications: 5 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=-0.51).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5	c.170-971G>A		intron_variant	Intron 1 of 2	ENST00000265340.12	NP_002644.4
PITX1	XM_047417318.1	c.272-971G>A		intron_variant	Intron 2 of 3		XP_047273274.1
PITX1	XM_047417319.1	c.-177+959G>A		intron_variant	Intron 1 of 2		XP_047273275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12	c.170-971G>A		intron_variant	Intron 1 of 2	1	NM_002653.5	ENSP00000265340.6

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30223 AN: 151990 Hom.: 4563 Cov.: 33

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.0670

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

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

GnomAD4 genome AF: 0.199 AC: 30331 AN: 152108 Hom.: 4598 Cov.: 33 AF XY: 0.192 AC XY: 14296 AN XY: 74376

African (AFR) AF: 0.424 AC: 17563 AN: 41444

American (AMR) AF: 0.207 AC: 3163 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0670 AC: 232 AN: 3464

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5188

South Asian (SAS) AF: 0.0514 AC: 248 AN: 4822

European-Finnish (FIN) AF: 0.0755 AC: 799 AN: 10584

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

European-Non Finnish (NFE) AF: 0.116 AC: 7871 AN: 68000

Other (OTH) AF: 0.189 AC: 399 AN: 2110

Alfa AF: 0.149 Hom.: 6513

Bravo AF: 0.221

Asia WGS AF: 0.0520 AC: 181 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.90
PhyloP100		-0.27
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: rs6596189; hg19: chr5-134368169;