5-135028931-C-A

Variant names:

• chr5-135028931-C-A
• rs141612135
• NM_002653.5:c.793G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_002653.5(PITX1):​c.793G>T​(p.Gly265Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G265S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PITX1 NM_002653.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.02
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797
• PP5: Variant 5-135028931-C-A is Pathogenic according to our data. Variant chr5-135028931-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 932171.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5	c.793G>T	p.Gly265Cys	missense_variant	Exon 3 of 3	ENST00000265340.12	NP_002644.4
PITX1	XM_047417318.1	c.895G>T	p.Gly299Cys	missense_variant	Exon 4 of 4		XP_047273274.1
PITX1	XM_047417319.1	c.448G>T	p.Gly150Cys	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.793G>T	p.Gly265Cys	missense_variant	Exon 3 of 3	1	NM_002653.5	ENSP00000265340.6
PITX1	ENST00000506438.5	c.793G>T	p.Gly265Cys	missense_variant	Exon 4 of 4	1		ENSP00000427542.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Micrognathia Pathogenic:1

Jun 27, 2016

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PM2, PP3, PP4 -

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		6.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.050	T;T
Polyphen		1.0	D;D
Vest4		0.53
MutPred		0.22		Gain of catalytic residue at S269 (P = 0.0648);Gain of catalytic residue at S269 (P = 0.0648);
MVP		0.95
MPC		2.2
ClinPred		0.98	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56
gMVP		0.79
Mutation Taster		=45/55	disease causing (ClinVar)

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: rs141612135; hg19: chr5-134364621;