10-95321967-C-T

Position:

• chr10-95321967-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001034954.3(SORBS1):​c.3694G>A​(p.Asp1232Asn) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SORBS1 NM_001034954.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

Genes affected

SORBS1 (HGNC:14565): (sorbin and SH3 domain containing 1) This gene encodes a CBL-associated protein which functions in the signaling and stimulation of insulin. Mutations in this gene may be associated with human disorders of insulin resistance. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26861778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SORBS1	NM_001034954.3	c.3694G>A	p.Asp1232Asn	missense_variant	31/33	ENST00000371247.7	NP_001030126.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORBS1	ENST00000371247.7	c.3694G>A	p.Asp1232Asn	missense_variant	31/33	5	NM_001034954.3	ENSP00000360293.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.3694G>A (p.D1232N) alteration is located in exon 29 (coding exon 29) of the SORBS1 gene. This alteration results from a G to A substitution at nucleotide position 3694, causing the aspartic acid (D) at amino acid position 1232 to be replaced by an asparagine (N). 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	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	.;.;.;.;.;T;.;.;.;T;.;.;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;.;.;D;D;D;D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.33	.;.;.;.;.;N;.;.;.;N;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D;.;D;D;D;D;.;.;.;D;D;D;D;D;D
REVEL	Benign	0.093
Sift	Uncertain	0.018	D;.;D;D;T;D;.;.;.;D;T;D;D;D;D
Sift4G	Uncertain	0.020	D;.;T;T;T;D;D;.;.;D;T;T;T;D;T
Polyphen		1.0	D;.;B;P;B;D;.;.;.;D;B;D;B;D;D
Vest4		0.29
MutPred		0.28		.;.;.;.;.;Gain of MoRF binding (P = 0.0619);.;.;.;Gain of MoRF binding (P = 0.0619);.;.;.;.;.;
MVP		0.67
MPC		0.36
ClinPred		0.77	D
GERP RS		6.1
Varity_R		0.17
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1172336868; hg19: chr10-97081724;