5-135033815-G-A

Variant names:

• chr5-135033815-G-A
• NM_002653.5:c.67C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002653.5(PITX1):​c.67C>T​(p.Pro23Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,383,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: PITX1 NM_002653.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

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-AS1 (HGNC:48332): (PITX1 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1915327).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5	c.67C>T	p.Pro23Ser	missense_variant	Exon 1 of 3	ENST00000265340.12	NP_002644.4
PITX1	XM_047417318.1	c.169C>T	p.Pro57Ser	missense_variant	Exon 2 of 4		XP_047273274.1
PITX1-AS1	NR_161235.1	n.267+275G>A		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12	c.67C>T	p.Pro23Ser	missense_variant	Exon 1 of 3	1	NM_002653.5	ENSP00000265340.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000434 AC: 6 AN: 1383888 Hom.: 0 Cov.: 31 AF XY: 0.00000729 AC XY: 5 AN XY: 685982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.0000696

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.67C>T (p.P23S) alteration is located in exon 1 (coding exon 1) of the PITX1 gene. This alteration results from a C to T substitution at nucleotide position 67, causing the proline (P) at amino acid position 23 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T;.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.50	.;T;T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.76	N;N;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.17	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.47	T;T;T;T
Sift4G	Benign	0.95	T;T;.;T
Polyphen		0.0060	B;B;.;.
Vest4		0.20
MutPred		0.28		Gain of phosphorylation at P23 (P = 0.006);Gain of phosphorylation at P23 (P = 0.006);Gain of phosphorylation at P23 (P = 0.006);Gain of phosphorylation at P23 (P = 0.006);
MVP		0.93
MPC		1.0
ClinPred		0.19	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Varity_R		0.055
gMVP		0.37

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-134369505;