chr3-18349483-TGGAGGATTCCCAAGGCTTCCACTGAAATTTTTGTTCGTGGCCGGGTCTTCTGTCGGTTTTCCTCATCTGACTCTGCTGGAGAGGCCACCGTGGGTTGCCGTGG-T

Variant names:

• chr3-18349483-TGGAGGATTCCCAAGGCTTCCACTGAAATTTTTGTTCGTGGCCGGGTCTTCTGTCGGTTTTCCTCATCTGACTCTGCTGGAGAGGCCACCGTGGGTTGCCGTGG-T
• rs2125122990
• NM_002971.6:c.1876_1978del

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_002971.6(SATB1):​c.1876_1978del​(p.Pro626ArgfsTer47) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SATB1 NM_002971.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.79
• Publications: 0 publications found

Genes affected

SATB1 (HGNC:10541): (SATB homeobox 1) This gene encodes a matrix protein which binds nuclear matrix and scaffold-associating DNAs through a unique nuclear architecture. The protein recruits chromatin-remodeling factors in order to regulate chromatin structure and gene expression. [provided by RefSeq, Apr 2016]

TBC1D5 (HGNC:19166): (TBC1 domain family member 5) Enables AP-2 adaptor complex binding activity and retromer complex binding activity. Involved in several processes, including macroautophagy; positive regulation of receptor internalization; and retrograde transport, endosome to Golgi. Located in Golgi apparatus; autophagosome; and endosome membrane. Part of retromer complex. Colocalizes with AP-2 adaptor complex and Atg1/ULK1 kinase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PP5: Variant 3-18349483-TGGAGGATTCCCAAGGCTTCCACTGAAATTTTTGTTCGTGGCCGGGTCTTCTGTCGGTTTTCCTCATCTGACTCTGCTGGAGAGGCCACCGTGGGTTGCCGTGG-T is Pathogenic according to our data. Variant chr3-18349483-TGGAGGATTCCCAAGGCTTCCACTGAAATTTTTGTTCGTGGCCGGGTCTTCTGTCGGTTTTCCTCATCTGACTCTGCTGGAGAGGCCACCGTGGGTTGCCGTGG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1700168.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002971.6. 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
	SATB1	NM_002971.6	MANE Select	c.1876_1978del	p.Pro626ArgfsTer47	frameshift	Exon 11 of 11	NP_002962.1	Q01826-1
	SATB1	NM_001195470.3		c.1972_2074del	p.Pro658ArgfsTer47	frameshift	Exon 12 of 12	NP_001182399.1	Q01826-2
	SATB1	NM_001322871.2		c.1972_2074del	p.Pro658ArgfsTer47	frameshift	Exon 12 of 12	NP_001309800.1	Q01826-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SATB1	ENST00000338745.11	TSL:1 MANE Select	c.1876_1978del	p.Pro626ArgfsTer47	frameshift	Exon 11 of 11	ENSP00000341024.5	Q01826-1
	SATB1	ENST00000417717.6	TSL:1	c.1972_2074del	p.Pro658ArgfsTer47	frameshift	Exon 12 of 12	ENSP00000399518.1	Q01826-2
	SATB1	ENST00000454909.6	TSL:1	c.1876_1978del	p.Pro626ArgfsTer47	frameshift	Exon 11 of 11	ENSP00000399708.2	Q01826-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2125122990; hg19: chr3-18390975;