5-135028828-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002653.5(PITX1):c.896G>C(p.Gly299Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,611,896 control chromosomes in the GnomAD database, including 61,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5044 hom., cov: 33)
  • Exomes 𝑓: 0.27 (56215 hom.)
• Consequence: PITX1 NM_002653.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00277856).
• BP6: Variant 5-135028828-C-G is Benign according to our data. Variant chr5-135028828-C-G is described in ClinVar as [Benign]. Clinvar id is 286868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-135028828-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITX1	NM_002653.5	c.896G>C	p.Gly299Ala	missense_variant	3/3	ENST00000265340.12
PITX1	XM_047417318.1	c.998G>C	p.Gly333Ala	missense_variant	4/4
PITX1	XM_047417319.1	c.551G>C	p.Gly184Ala	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITX1	ENST00000265340.12	c.896G>C	p.Gly299Ala	missense_variant	3/3	1	NM_002653.5	P1
PITX1	ENST00000506438.5	c.896G>C	p.Gly299Ala	missense_variant	4/4	1		P1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 36998 AN: 151880 Hom.: 5044 Cov.: 33

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.229

GnomAD3 exomes AF: 0.292 AC: 71893 AN: 246276 Hom.: 11240 AF XY: 0.295 AC XY: 39475 AN XY: 133960

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.467

Gnomad SAS exome AF: 0.382

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.270 AC: 393595 AN: 1459906 Hom.: 56215 Cov.: 37 AF XY: 0.273 AC XY: 198473 AN XY: 726260

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.242

Gnomad4 EAS exome AF: 0.543

Gnomad4 SAS exome AF: 0.385

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.274

GnomAD4 genome AF: 0.243 AC: 37002 AN: 151990 Hom.: 5044 Cov.: 33 AF XY: 0.247 AC XY: 18356 AN XY: 74306

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.282

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.414

Gnomad4 FIN AF: 0.251

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.233

Alfa AF: 0.223 Hom.: 1333

Bravo AF: 0.239

ESP6500AA AF: 0.155 AC: 685

ESP6500EA AF: 0.248 AC: 2132

ExAC AF: 0.285 AC: 34590

EpiCase AF: 0.258

EpiControl AF: 0.250

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Clubfoot Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Brachydactyly-elbow wrist dysplasia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	25
Dann	Benign	0.94
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.071
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.045	N;N
MutationTaster	Benign	0.000082	P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.98	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.75	T;T
Sift4G	Benign	0.77	T;T
Polyphen		0.15	B;B
Vest4		0.076
MPC		1.1
ClinPred		0.030	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.10
gMVP		0.42

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: rs479632; hg19: chr5-134364518; COSMIC: COSV54761809; COSMIC: COSV54761809;