rs777634577

Variant names:

• chr5-135033724-G-A
• rs777634577
• NM_002653.5:c.158C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002653.5(PITX1):​c.158C>T​(p.Thr53Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000094 in 1,596,244 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: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: PITX1 NM_002653.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.54
• 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-AS1 (HGNC:48332): (PITX1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35705215).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002653.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX1	NM_002653.5	MANE Select	c.158C>T	p.Thr53Met	missense	Exon 1 of 3	NP_002644.4
	PITX1-AS1	NR_161235.1		n.267+184G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX1	ENST00000265340.12	TSL:1 MANE Select	c.158C>T	p.Thr53Met	missense	Exon 1 of 3	ENSP00000265340.6	P78337
	PITX1	ENST00000506438.5	TSL:1	c.158C>T	p.Thr53Met	missense	Exon 2 of 4	ENSP00000427542.1	P78337
	PITX1	ENST00000507253.5	TSL:3	c.158C>T	p.Thr53Met	missense	Exon 2 of 3	ENSP00000422908.1	D6R9U1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000457 AC: 10 AN: 219016 AF XY: 0.0000327

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000900 AC: 13 AN: 1444140 Hom.: 0 Cov.: 31 AF XY: 0.00000556 AC XY: 4 AN XY: 718888

African (AFR) AF: 0.00 AC: 0 AN: 32822

American (AMR) AF: 0.000202 AC: 9 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39372

South Asian (SAS) AF: 0.00 AC: 0 AN: 85698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5172

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109560

Other (OTH) AF: 0.0000167 AC: 1 AN: 59892

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000281 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000425 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Clubfoot (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.40
Sift	Benign	0.085	T
Sift4G	Benign	0.077	T
Polyphen		0.96	D
Vest4		0.29
MutPred		0.17		Loss of phosphorylation at T53 (P = 0.0118)
MVP		0.95
MPC		1.1
ClinPred		0.43	T
GERP RS		3.4
Varity_R		0.10
gMVP		0.43
Mutation Taster		=76/24	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: rs777634577; hg19: chr5-134369414;