rs1131611

Variant names:

• chr5-135029306-G-T
• rs1131611
• NM_002653.5:c.418C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002653.5(PITX1):​c.418C>A​(p.Arg140Arg) 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
• Publications: 10 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 -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 VariationId is 285760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 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.418C>A	p.Arg140Arg	synonymous	Exon 3 of 3	NP_002644.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX1	ENST00000265340.12	TSL:1 MANE Select	c.418C>A	p.Arg140Arg	synonymous	Exon 3 of 3	ENSP00000265340.6	P78337
	PITX1	ENST00000506438.5	TSL:1	c.418C>A	p.Arg140Arg	synonymous	Exon 4 of 4	ENSP00000427542.1	P78337
	PITX1	ENST00000503586.1	TSL:3	n.540C>A		non_coding_transcript_exon	Exon 3 of 3

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

GnomAD2 exomes AF: 0.123 AC: 28929 AN: 235206 AF XY: 0.113

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 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

African (AFR) AF: 0.427 AC: 14099 AN: 33026

American (AMR) AF: 0.196 AC: 8573 AN: 43704

Ashkenazi Jewish (ASJ) AF: 0.0670 AC: 1667 AN: 24888

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39518

South Asian (SAS) AF: 0.0492 AC: 4102 AN: 83344

European-Finnish (FIN) AF: 0.0812 AC: 4258 AN: 52438

Middle Eastern (MID) AF: 0.0705 AC: 401 AN: 5686

European-Non Finnish (NFE) AF: 0.120 AC: 131827 AN: 1102870

Other (OTH) AF: 0.124 AC: 7421 AN: 59652

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

African (AFR) AF: 0.424 AC: 17574 AN: 41488

American (AMR) AF: 0.207 AC: 3161 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 233 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5178

South Asian (SAS) AF: 0.0512 AC: 247 AN: 4828

European-Finnish (FIN) AF: 0.0755 AC: 802 AN: 10618

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

European-Non Finnish (NFE) AF: 0.116 AC: 7866 AN: 68012

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

Alfa AF: 0.146 Hom.: 3297

Bravo AF: 0.221

Asia WGS AF: 0.0520 AC: 182 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		6.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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