10-95336906-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001034954.3(SORBS1):c.3254C>T(p.Ser1085Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SORBS1 NM_001034954.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09530988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORBS1	NM_001034954.3	c.3254C>T	p.Ser1085Leu	missense_variant	30/33	ENST00000371247.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORBS1	ENST00000371247.7	c.3254C>T	p.Ser1085Leu	missense_variant	30/33	5	NM_001034954.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249472 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134960

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461070 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 06, 2021

The c.3254C>T (p.S1085L) alteration is located in exon 28 (coding exon 28) of the SORBS1 gene. This alteration results from a C to T substitution at nucleotide position 3254, causing the serine (S) at amino acid position 1085 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	Benign	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Uncertain	0.98
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.64	T;T;T;.
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.095	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N;N;.;N
REVEL	Benign	0.058
Sift	Benign	0.053	T;D;.;D
Sift4G	Benign	0.69	T;T;.;T
Polyphen		0.038	B;B;.;B
Vest4		0.24
MutPred		0.28		.;Loss of glycosylation at S1085 (P = 0.0072);.;Loss of glycosylation at S1085 (P = 0.0072);
MVP		0.50
MPC		0.17
ClinPred		0.13	T
GERP RS		5.0
Varity_R		0.088
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs1475396735; hg19: chr10-97096663; COSMIC: COSV53362523; COSMIC: COSV53362523;