5-135028828-C-G

Variant names:

• chr5-135028828-C-G
• rs479632
• NM_002653.5:c.896G>C

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G299V) has been classified as Uncertain significance.

• 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
• Publications: 34 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 Gene-Disease associations (from GenCC):

• clubfoot

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• brachydactyly-elbow wrist dysplasia syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 286868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

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.896G>C	p.Gly299Ala	missense	Exon 3 of 3	NP_002644.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX1	ENST00000265340.12	TSL:1 MANE Select	c.896G>C	p.Gly299Ala	missense	Exon 3 of 3	ENSP00000265340.6	P78337
	PITX1	ENST00000506438.5	TSL:1	c.896G>C	p.Gly299Ala	missense	Exon 4 of 4	ENSP00000427542.1	P78337

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

GnomAD2 exomes AF: 0.292 AC: 71893 AN: 246276 AF XY: 0.295

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 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

African (AFR) AF: 0.158 AC: 5277 AN: 33452

American (AMR) AF: 0.338 AC: 15061 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6319 AN: 26104

East Asian (EAS) AF: 0.543 AC: 21544 AN: 39650

South Asian (SAS) AF: 0.385 AC: 33175 AN: 86202

European-Finnish (FIN) AF: 0.257 AC: 13556 AN: 52720

Middle Eastern (MID) AF: 0.255 AC: 1410 AN: 5528

European-Non Finnish (NFE) AF: 0.253 AC: 280770 AN: 1111372

Other (OTH) AF: 0.274 AC: 16483 AN: 60254

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

African (AFR) AF: 0.157 AC: 6527 AN: 41522

American (AMR) AF: 0.282 AC: 4318 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 817 AN: 3466

East Asian (EAS) AF: 0.471 AC: 2409 AN: 5118

South Asian (SAS) AF: 0.414 AC: 1997 AN: 4828

European-Finnish (FIN) AF: 0.251 AC: 2651 AN: 10548

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.256 AC: 17407 AN: 67898

Other (OTH) AF: 0.233 AC: 492 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Brachydactyly-elbow wrist dysplasia syndrome (1)
-	-	1	Clubfoot (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.071
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.045	N
PhyloP100		7.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.98	N
REVEL	Uncertain	0.36
Sift	Benign	0.75	T
Sift4G	Benign	0.77	T
Polyphen		0.15	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
Mutation Taster		=94/6	polymorphism (auto)

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