NM_002971.6:c.2219T>C

Variant names:

• chr3-18349243-A-G
• NM_002971.6:c.2219T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002971.6(SATB1):​c.2219T>C​(p.Leu740Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L740I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SATB1 NM_002971.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.54
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38962162).

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.2219T>C	p.Leu740Pro	missense	Exon 11 of 11	NP_002962.1	Q01826-1
	SATB1	NM_001195470.3		c.2315T>C	p.Leu772Pro	missense	Exon 12 of 12	NP_001182399.1	Q01826-2
	SATB1	NM_001322871.2		c.2315T>C	p.Leu772Pro	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.2219T>C	p.Leu740Pro	missense	Exon 11 of 11	ENSP00000341024.5	Q01826-1
	SATB1	ENST00000417717.6	TSL:1	c.2315T>C	p.Leu772Pro	missense	Exon 12 of 12	ENSP00000399518.1	Q01826-2
	SATB1	ENST00000454909.6	TSL:1	c.2219T>C	p.Leu740Pro	missense	Exon 11 of 11	ENSP00000399708.2	Q01826-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.34	N
PhyloP100		6.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.34	T
Polyphen		0.96	D
Vest4		0.33
MutPred		0.36		Gain of loop (P = 0.0097)
MVP		0.72
MPC		2.5
ClinPred		0.87	D
GERP RS		5.6
Varity_R		0.63
gMVP		0.76
Mutation Taster		=39/61	disease causing

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

hg19: chr3-18390735;