chr5-135033805-T-G

Position:

• chr5-135033805-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002653.5(PITX1):​c.77A>C​(p.Asp26Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PITX1 NM_002653.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.53

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITX1	NM_002653.5	c.77A>C	p.Asp26Ala	missense_variant	1/3	ENST00000265340.12
PITX1-AS1	NR_161235.1	n.267+265T>G		intron_variant, non_coding_transcript_variant
PITX1	XM_047417318.1	c.179A>C	p.Asp60Ala	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITX1	ENST00000265340.12	c.77A>C	p.Asp26Ala	missense_variant	1/3	1	NM_002653.5	P1
PITX1-AS1	ENST00000624272.3	n.261+265T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 19, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;.;T
Eigen	Benign	-0.017
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.43	.;T;T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Uncertain	0.092	D
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.25	T;T;T;T
Sift4G	Benign	0.65	T;T;.;T
Polyphen		0.82	P;P;.;.
Vest4		0.35
MutPred		0.25		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.99
MPC		1.9
ClinPred		0.96	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.27
gMVP		0.54

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: chr5-134369495;