rs1131611

Positions:

• chr5-135029306-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002653.5(PITX1):​c.418C>A​(p.Arg140=) variant causes a synonymous change. The variant allele was found at a frequency of 0.127 in 1,597,336 control chromosomes in the GnomAD database, including 17,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4603 hom., cov: 34)
  • Exomes 𝑓: 0.12 (12805 hom.)
• Consequence: PITX1 NM_002653.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.58

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-135029306-G-T is Benign according to our data. Variant chr5-135029306-G-T is described in ClinVar as [Benign]. Clinvar id is 285760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-135029306-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITX1	NM_002653.5	c.418C>A	p.Arg140=	synonymous_variant	3/3	ENST00000265340.12
PITX1	XM_047417318.1	c.520C>A	p.Arg174=	synonymous_variant	4/4
PITX1	XM_047417319.1	c.73C>A	p.Arg25=	synonymous_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITX1	ENST00000265340.12	c.418C>A	p.Arg140=	synonymous_variant	3/3	1	NM_002653.5	P1
PITX1	ENST00000506438.5	c.418C>A	p.Arg140=	synonymous_variant	4/4	1		P1
PITX1	ENST00000503586.1	n.540C>A		non_coding_transcript_exon_variant	3/3	3
PITX1	ENST00000504936.1	n.751C>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30230 AN: 152092 Hom.: 4568 Cov.: 34

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.0671

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0499

Gnomad FIN AF: 0.0755

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.191

GnomAD3 exomes AF: 0.123 AC: 28929 AN: 235206 Hom.: 2911 AF XY: 0.113 AC XY: 14357 AN XY: 127284

Gnomad AFR exome AF: 0.433

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.0665

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0481

Gnomad FIN exome AF: 0.0807

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.119 AC: 172354 AN: 1445126 Hom.: 12805 Cov.: 35 AF XY: 0.116 AC XY: 83050 AN XY: 716832

Gnomad4 AFR exome AF: 0.427

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.0670

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0492

Gnomad4 FIN exome AF: 0.0812

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.199 AC: 30338 AN: 152210 Hom.: 4603 Cov.: 34 AF XY: 0.192 AC XY: 14301 AN XY: 74444

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.0671

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0512

Gnomad4 FIN AF: 0.0755

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.189

Alfa AF: 0.136 Hom.: 2229

Bravo AF: 0.221

Asia WGS AF: 0.0520 AC: 182 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1131611; hg19: chr5-134364996; COSMIC: COSV54761597; COSMIC: COSV54761597;