rs2281939

Positions:

• chr10-95414595-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001034954.3(SORBS1):​c.709A>G​(p.Thr237Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0683 in 1,605,834 control chromosomes in the GnomAD database, including 6,871 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T237M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (2113 hom., cov: 31)
  • Exomes 𝑓: 0.063 (4758 hom.)
• Consequence: SORBS1 NM_001034954.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034773946).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORBS1	NM_001034954.3	c.709A>G	p.Thr237Ala	missense_variant	9/33	ENST00000371247.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORBS1	ENST00000371247.7	c.709A>G	p.Thr237Ala	missense_variant	9/33	5	NM_001034954.3	P3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18736 AN: 151882 Hom.: 2111 Cov.: 31

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0789

Gnomad ASJ AF: 0.0854

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.00896

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.0477

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.0822 AC: 20047 AN: 243874 Hom.: 1468 AF XY: 0.0817 AC XY: 10736 AN XY: 131484

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.0567

Gnomad ASJ exome AF: 0.0932

Gnomad EAS exome AF: 0.128

Gnomad SAS exome AF: 0.145

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0465

Gnomad OTH exome AF: 0.0732

GnomAD4 exome AF: 0.0625 AC: 90870 AN: 1453834 Hom.: 4758 Cov.: 32 AF XY: 0.0643 AC XY: 46464 AN XY: 722148

Gnomad4 AFR exome AF: 0.311

Gnomad4 AMR exome AF: 0.0586

Gnomad4 ASJ exome AF: 0.0903

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.0475

Gnomad4 OTH exome AF: 0.0840

GnomAD4 genome AF: 0.123 AC: 18771 AN: 152000 Hom.: 2113 Cov.: 31 AF XY: 0.121 AC XY: 9001 AN XY: 74310

Gnomad4 AFR AF: 0.298

Gnomad4 AMR AF: 0.0788

Gnomad4 ASJ AF: 0.0854

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.00896

Gnomad4 NFE AF: 0.0477

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0869 Hom.: 669

Bravo AF: 0.135

TwinsUK AF: 0.0550 AC: 204

ALSPAC AF: 0.0540 AC: 208

ESP6500AA AF: 0.305 AC: 1344

ESP6500EA AF: 0.0516 AC: 444

ExAC AF: 0.0856 AC: 10392

Asia WGS AF: 0.143 AC: 495 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.71
DEOGEN2	Benign	0.17	.;.;.;T;T;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.86	D;D;D;T;.;.;T;T
MetaRNN	Benign	0.0035	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.2	M;.;M;M;M;M;.;.
MutationTaster	Benign	0.98	P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N
REVEL	Benign	0.034
Sift	Uncertain	0.0080	D;D;D;D;D;D;T;D
Sift4G	Benign	0.57	T;T;T;T;T;T;T;T
Polyphen		0.79	P;B;P;B;B;P;P;.
Vest4		0.12
MPC		0.19
ClinPred		0.012	T
GERP RS		1.8
Varity_R		0.067
gMVP		0.16

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: rs2281939; hg19: chr10-97174352; COSMIC: COSV53357011; COSMIC: COSV53357011;