5-135033743-C-A

Variant names:

• chr5-135033743-C-A
• rs780516973
• NM_002653.5:c.139G>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_002653.5(PITX1):​c.139G>T​(p.Ala47Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,443,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PITX1 NM_002653.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18234721).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5	c.139G>T	p.Ala47Ser	missense_variant	Exon 1 of 3	ENST00000265340.12	NP_002644.4
PITX1	XM_047417318.1	c.241G>T	p.Ala81Ser	missense_variant	Exon 2 of 4		XP_047273274.1
PITX1-AS1	NR_161235.1	n.267+203C>A		intron_variant	Intron 1 of 5
PITX1	XM_047417319.1	c.-482G>T		upstream_gene_variant			XP_047273275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12	c.139G>T	p.Ala47Ser	missense_variant	Exon 1 of 3	1	NM_002653.5	ENSP00000265340.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000461 AC: 1 AN: 217076 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 121488

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1443678 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718566

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: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000858 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 19, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; 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	0.084
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T;T;.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	.;T;T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.90	L;L;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.26	N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.81	T;T;T;T
Sift4G	Benign	0.75	T;T;.;T
Polyphen		0.0030	B;B;.;.
Vest4		0.15
MutPred		0.18		Gain of phosphorylation at A47 (P = 0.0024);Gain of phosphorylation at A47 (P = 0.0024);Gain of phosphorylation at A47 (P = 0.0024);Gain of phosphorylation at A47 (P = 0.0024);
MVP		0.73
MPC		0.96
ClinPred		0.45	T
GERP RS		3.3
Varity_R		0.15
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs780516973; hg19: chr5-134369433;