rs762713626

Variant names:

• chr2-161420222-C-A
• rs762713626
• NM_006593.4:c.1155C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-161420222-C-A
• chr2-161420222-C-G
• chr2-161420222-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP3_Strong

The NM_006593.4(TBR1):​c.1155C>A​(p.Asn385Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBR1 NM_006593.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.0350
• Publications: 0 publications found

Genes affected

TBR1 (HGNC:11590): (T-box brain transcription factor 1) This gene is a member of a conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of numerous developmental processes. In mouse, the ortholog of this gene is expressed in the cerebral cortex, hippocampus, amygdala and olfactory bulb and is thought to play an important role in neuronal migration and axonal projection. In mouse, the C-terminal region of this protein was found to be necessary and sufficient for association with the guanylate kinase domain of calcium/calmodulin-dependent serine protein kinase. [provided by RefSeq, Dec 2015]

TBR1 Gene-Disease associations (from GenCC):

• autism

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• occipital pachygyria and polymicrogyria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS1: Transcript NM_006593.4 (TBR1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_006593.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBR1	NM_006593.4	c.1155C>A	p.Asn385Lys	missense_variant	Exon 5 of 6	ENST00000389554.8	NP_006584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBR1	ENST00000389554.8	c.1155C>A	p.Asn385Lys	missense_variant	Exon 5 of 6	1	NM_006593.4	ENSP00000374205.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autism, susceptibility to, 5 Uncertain:1

Jul 12, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.1	H;.;.
PhyloP100		0.035
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.92
MutPred		0.89		Loss of ubiquitination at K389 (P = 0.0347);.;.;
MVP		0.77
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.90
gMVP		0.98
Mutation Taster		=11/89	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

dbSNP: rs762713626; hg19: chr2-162276733;