5-135031850-A-G

Variant names:

• chr5-135031850-A-G
• rs11959298
• NM_002653.5:c.170-342T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002653.5(PITX1):​c.170-342T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 386,436 control chromosomes in the GnomAD database, including 10,269 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (7589 hom., cov: 33)
  • Exomes 𝑓: 0.12 (2680 hom.)
• Consequence: PITX1 NM_002653.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX1	NM_002653.5	MANE Select	c.170-342T>C		intron	N/A	NP_002644.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX1	ENST00000265340.12	TSL:1 MANE Select	c.170-342T>C		intron	N/A	ENSP00000265340.6
	PITX1	ENST00000506438.5	TSL:1	c.170-342T>C		intron	N/A	ENSP00000427542.1
	PITX1	ENST00000504936.1	TSL:2	n.161T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36402 AN: 151932 Hom.: 7547 Cov.: 33

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.0673

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0512

Gnomad FIN AF: 0.0755

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.218

GnomAD4 exome AF: 0.119 AC: 27998 AN: 234386 Hom.: 2680 Cov.: 0 AF XY: 0.114 AC XY: 13821 AN XY: 121232

African (AFR) AF: 0.555 AC: 4117 AN: 7416

American (AMR) AF: 0.212 AC: 1689 AN: 7968

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 525 AN: 7408

East Asian (EAS) AF: 0.000139 AC: 2 AN: 14348

South Asian (SAS) AF: 0.0551 AC: 1259 AN: 22866

European-Finnish (FIN) AF: 0.0814 AC: 1144 AN: 14058

Middle Eastern (MID) AF: 0.0845 AC: 96 AN: 1136

European-Non Finnish (NFE) AF: 0.119 AC: 17232 AN: 145134

Other (OTH) AF: 0.138 AC: 1934 AN: 14052

GnomAD4 genome AF: 0.240 AC: 36527 AN: 152050 Hom.: 7589 Cov.: 33 AF XY: 0.232 AC XY: 17214 AN XY: 74348

African (AFR) AF: 0.564 AC: 23408 AN: 41488

American (AMR) AF: 0.223 AC: 3408 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0673 AC: 233 AN: 3460

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5178

South Asian (SAS) AF: 0.0522 AC: 251 AN: 4804

European-Finnish (FIN) AF: 0.0755 AC: 798 AN: 10574

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7911 AN: 67942

Other (OTH) AF: 0.217 AC: 458 AN: 2114

Alfa AF: 0.186 Hom.: 1555

Bravo AF: 0.267

Asia WGS AF: 0.0640 AC: 225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.82
DANN	Benign	0.65
PhyloP100		-1.4
Mutation Taster		=100/0	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: rs11959298; hg19: chr5-134367540;