3-18349244-G-A

Variant names:

• chr3-18349244-G-A
• rs1329953084
• NM_002971.6:c.2218C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002971.6(SATB1):​c.2218C>T​(p.Leu740Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L740P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SATB1 NM_002971.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.13
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22095546).

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.2218C>T	p.Leu740Phe	missense	Exon 11 of 11	NP_002962.1	Q01826-1
	SATB1	NM_001195470.3		c.2314C>T	p.Leu772Phe	missense	Exon 12 of 12	NP_001182399.1	Q01826-2
	SATB1	NM_001322871.2		c.2314C>T	p.Leu772Phe	missense	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.2218C>T	p.Leu740Phe	missense	Exon 11 of 11	ENSP00000341024.5	Q01826-1
	SATB1	ENST00000417717.6	TSL:1	c.2314C>T	p.Leu772Phe	missense	Exon 12 of 12	ENSP00000399518.1	Q01826-2
	SATB1	ENST00000454909.6	TSL:1	c.2218C>T	p.Leu740Phe	missense	Exon 11 of 11	ENSP00000399708.2	Q01826-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.17
Sift	Uncertain	0.010	D
Sift4G	Benign	0.37	T
Polyphen		0.51	P
Vest4		0.14
MutPred		0.29		Gain of catalytic residue at L740 (P = 0.0114)
MVP		0.27
MPC		1.6
ClinPred		0.66	D
GERP RS		5.5
Varity_R		0.15
gMVP		0.56
Mutation Taster		=90/10	polymorphism

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: rs1329953084; hg19: chr3-18390736; COSMIC: COSV58668576; COSMIC: COSV58668576;