5-135033803-T-C

Variant names:

• chr5-135033803-T-C
• NM_002653.5:c.79A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002653.5(PITX1):​c.79A>G​(p.Met27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,416,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 0.0000028 (0 hom.)
• Consequence: PITX1 NM_002653.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.32
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23842621).

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.79A>G	p.Met27Val	missense	Exon 1 of 3	NP_002644.4
	PITX1-AS1	NR_161235.1		n.267+263T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX1	ENST00000265340.12	TSL:1 MANE Select	c.79A>G	p.Met27Val	missense	Exon 1 of 3	ENSP00000265340.6	P78337
	PITX1	ENST00000506438.5	TSL:1	c.79A>G	p.Met27Val	missense	Exon 2 of 4	ENSP00000427542.1	P78337
	PITX1	ENST00000507253.5	TSL:3	c.79A>G	p.Met27Val	missense	Exon 2 of 3	ENSP00000422908.1	D6R9U1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1416452 Hom.: 0 Cov.: 31 AF XY: 0.00000426 AC XY: 3 AN XY: 703732

African (AFR) AF: 0.00 AC: 0 AN: 29932

American (AMR) AF: 0.00 AC: 0 AN: 41328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25026

East Asian (EAS) AF: 0.00 AC: 0 AN: 36640

South Asian (SAS) AF: 0.00 AC: 0 AN: 82594

European-Finnish (FIN) AF: 0.0000250 AC: 1 AN: 39976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4148

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1098164

Other (OTH) AF: 0.00 AC: 0 AN: 58644

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.22
Sift	Benign	0.087	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.19		Loss of catalytic residue at M27 (P = 0.1047)
MVP		0.94
MPC		1.0
ClinPred		0.35	T
GERP RS		1.3
PromoterAI		0.033	Neutral
Varity_R		0.25
gMVP		0.20
Mutation Taster		=92/8	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

hg19: chr5-134369493;