chr5-135031850-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002653.5(PITX1):​c.170-342T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 234,726 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PITX1 NM_002653.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• 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 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

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.170-342T>G		intron	N/A	NP_002644.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX1	ENST00000265340.12	TSL:1 MANE Select	c.170-342T>G		intron	N/A	ENSP00000265340.6	P78337
	PITX1	ENST00000506438.5	TSL:1	c.170-342T>G		intron	N/A	ENSP00000427542.1	P78337
	PITX1	ENST00000507253.5	TSL:3	c.170-342T>G		intron	N/A	ENSP00000422908.1	D6R9U1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000128 AC: 3 AN: 234726 Hom.: 0 Cov.: 0 AF XY: 0.0000165 AC XY: 2 AN XY: 121392

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 7440

American (AMR) AF: 0.00 AC: 0 AN: 7990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7418

East Asian (EAS) AF: 0.0000697 AC: 1 AN: 14348

South Asian (SAS) AF: 0.00 AC: 0 AN: 22878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1136

European-Non Finnish (NFE) AF: 0.0000138 AC: 2 AN: 145358

Other (OTH) AF: 0.00 AC: 0 AN: 14086

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.70
DANN	Benign	0.70
PhyloP100		-1.4

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;