chr5-135029401-T-A

Variant names:

• chr5-135029401-T-A
• rs474853
• NM_002653.5:c.403-80A>T

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.403-80A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PITX1 NM_002653.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• Publications: 9 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: 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=-0.79).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5	c.403-80A>T		intron_variant	Intron 2 of 2	ENST00000265340.12	NP_002644.4
PITX1	XM_047417318.1	c.505-80A>T		intron_variant	Intron 3 of 3		XP_047273274.1
PITX1	XM_047417319.1	c.58-80A>T		intron_variant	Intron 2 of 2		XP_047273275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12	c.403-80A>T		intron_variant	Intron 2 of 2	1	NM_002653.5	ENSP00000265340.6
PITX1	ENST00000506438.5	c.403-80A>T		intron_variant	Intron 3 of 3	1		ENSP00000427542.1
PITX1	ENST00000503586.1	n.525-80A>T		intron_variant	Intron 2 of 2	3
PITX1	ENST00000504936.1	n.736-80A>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1069022 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 534182

African (AFR) AF: 0.00 AC: 0 AN: 23992

American (AMR) AF: 0.00 AC: 0 AN: 27972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18042

East Asian (EAS) AF: 0.00 AC: 0 AN: 37338

South Asian (SAS) AF: 0.00 AC: 0 AN: 62702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3432

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 801296

Other (OTH) AF: 0.00 AC: 0 AN: 46198

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.1
DANN	Benign	0.73
PhyloP100		-1.1

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: rs474853; hg19: chr5-134365091;