4-185589687-C-A

Variant names:

• chr4-185589687-C-A
• NM_001395207.1:c.3833G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001395207.1(SORBS2):​c.3833G>T​(p.Trp1278Leu) variant causes a missense change involving the alteration of a 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SORBS2 NM_001395207.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

SORBS2 (HGNC:24098): (sorbin and SH3 domain containing 2) Arg and c-Abl represent the mammalian members of the Abelson family of non-receptor protein-tyrosine kinases. They interact with the Arg/Abl binding proteins via the SH3 domains present in the carboxy end of the latter group of proteins. This gene encodes the sorbin and SH3 domain containing 2 protein. It has three C-terminal SH3 domains and an N-terminal sorbin homology (SoHo) domain that interacts with lipid raft proteins. The subcellular localization of this protein in epithelial and cardiac muscle cells suggests that it functions as an adapter protein to assemble signaling complexes in stress fibers, and that it is a potential link between Abl family kinases and the actin cytoskeleton. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

SORBS2-AS1 (HGNC:41039): (SORBS2 antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORBS2	NM_001395207.1	c.3833G>T	p.Trp1278Leu	missense_variant	Exon 26 of 27	ENST00000695409.1	NP_001382136.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORBS2	ENST00000695409.1	c.3833G>T	p.Trp1278Leu	missense_variant	Exon 26 of 27		NM_001395207.1	ENSP00000511888.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3233G>T (p.W1078L) alteration is located in exon 20 (coding exon 16) of the SORBS2 gene. This alteration results from a G to T substitution at nucleotide position 3233, causing the tryptophan (W) at amino acid position 1078 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	.;.;.;T;.;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	4.0	.;.;.;H;.;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-11	.;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	.;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	.;D;D;D;D;D;D;D;D
Polyphen		0.73, 0.99	.;.;.;P;.;.;.;.;D
Vest4		0.91, 0.94, 0.91, 0.95, 0.95, 0.94, 0.95, 0.96
MutPred		0.96		.;.;.;Gain of phosphorylation at S1083 (P = 0.1267);.;.;.;.;.;
MVP		0.69
MPC		1.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-186510841;