NM_002653.5:c.796A>C

Variant names:

• chr5-135028928-T-G
• rs1386538357
• NM_002653.5:c.796A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002653.5(PITX1):​c.796A>C​(p.Thr266Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T266A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PITX1 NM_002653.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.22
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042718053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5	c.796A>C	p.Thr266Pro	missense_variant	Exon 3 of 3	ENST00000265340.12	NP_002644.4
PITX1	XM_047417318.1	c.898A>C	p.Thr300Pro	missense_variant	Exon 4 of 4		XP_047273274.1
PITX1	XM_047417319.1	c.451A>C	p.Thr151Pro	missense_variant	Exon 3 of 3		XP_047273275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12	c.796A>C	p.Thr266Pro	missense_variant	Exon 3 of 3	1	NM_002653.5	ENSP00000265340.6
PITX1	ENST00000506438.5	c.796A>C	p.Thr266Pro	missense_variant	Exon 4 of 4	1		ENSP00000427542.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-1.5	N;N
PhyloP100		7.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	1.7	N;N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.091
MutPred		0.21		Loss of phosphorylation at T266 (P = 0.0062);Loss of phosphorylation at T266 (P = 0.0062);
MVP		0.78
MPC		1.3
ClinPred		0.62	D
GERP RS		3.0
Varity_R		0.29
gMVP		0.53
Mutation Taster		=55/45	polymorphism

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: rs1386538357; hg19: chr5-134364618;