rs141000980

Variant names:

• chr10-95318370-T-C
• rs141000980
• NM_001034954.3:c.3761A>G

Variant summary

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

The NM_001034954.3(SORBS1):​c.3761A>G​(p.Asp1254Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000563 in 1,455,692 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: SORBS1 NM_001034954.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORBS1	NM_001034954.3	c.3761A>G	p.Asp1254Gly	missense_variant	Exon 32 of 33	ENST00000371247.7	NP_001030126.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORBS1	ENST00000371247.7	c.3761A>G	p.Asp1254Gly	missense_variant	Exon 32 of 33	5	NM_001034954.3	ENSP00000360293.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 246880 Hom.: 0 AF XY: 0.00000750 AC XY: 1 AN XY: 133402

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000563 AC: 82 AN: 1455692 Hom.: 0 Cov.: 28 AF XY: 0.0000497 AC XY: 36 AN XY: 723976

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: 0.0000730

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3761A>G (p.D1254G) alteration is located in exon 30 (coding exon 30) of the SORBS1 gene. This alteration results from a A to G substitution at nucleotide position 3761, causing the aspartic acid (D) at amino acid position 1254 to be replaced by a glycine (G). 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	0.74
BayesDel_addAF	Benign	-0.0072	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;.;.;.;.;T;.;.;.;T;.;.;.;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;.;.;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.63	.;.;.;.;.;N;.;.;.;N;.;.;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.6	D;.;D;D;D;D;.;.;.;D;D;D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;.;D;D;D;D;.;.;.;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;.;D;D;D;D;D;.;.;D;D;D;D;D;D
Polyphen		1.0	D;.;P;D;D;D;.;.;.;D;D;D;D;D;D
Vest4		0.58
MVP		0.72
MPC		0.86
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.60

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: rs141000980; hg19: chr10-97078127;