chr10-95414595-T-C

Variant names:

• chr10-95414595-T-C
• rs2281939
• NM_001034954.3:c.709A>G

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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 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
• Publications: 34 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SORBS1	NM_001034954.3	c.709A>G	p.Thr237Ala	missense_variant	Exon 9 of 33	ENST00000371247.7	NP_001030126.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORBS1	ENST00000371247.7	c.709A>G	p.Thr237Ala	missense_variant	Exon 9 of 33	5	NM_001034954.3	ENSP00000360293.2

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

GnomAD2 exomes AF: 0.0822 AC: 20047 AN: 243874 AF XY: 0.0817

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 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

African (AFR) AF: 0.311 AC: 10390 AN: 33372

American (AMR) AF: 0.0586 AC: 2598 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.0903 AC: 2309 AN: 25572

East Asian (EAS) AF: 0.119 AC: 4732 AN: 39626

South Asian (SAS) AF: 0.141 AC: 11973 AN: 84812

European-Finnish (FIN) AF: 0.0119 AC: 632 AN: 52994

Middle Eastern (MID) AF: 0.107 AC: 612 AN: 5724

European-Non Finnish (NFE) AF: 0.0475 AC: 52575 AN: 1107294

Other (OTH) AF: 0.0840 AC: 5049 AN: 60074

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

African (AFR) AF: 0.298 AC: 12347 AN: 41420

American (AMR) AF: 0.0788 AC: 1203 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0854 AC: 296 AN: 3468

East Asian (EAS) AF: 0.124 AC: 639 AN: 5172

South Asian (SAS) AF: 0.139 AC: 665 AN: 4790

European-Finnish (FIN) AF: 0.00896 AC: 95 AN: 10606

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.0477 AC: 3239 AN: 67960

Other (OTH) AF: 0.114 AC: 240 AN: 2110

Alfa AF: 0.0929 Hom.: 985

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;.;.
PhyloP100		1.0
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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