10-95337020-C-T

Variant names:

• chr10-95337020-C-T
• rs193920900
• NM_001034954.3:c.3140G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001034954.3(SORBS1):​c.3140G>A​(p.Arg1047Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,569,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1047P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SORBS1 NM_001034954.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.420
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043346316).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034954.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORBS1	NM_001034954.3	MANE Select	c.3140G>A	p.Arg1047Gln	missense	Exon 30 of 33	NP_001030126.2	Q9BX66-1
	SORBS1	NM_001384452.1		c.4016G>A	p.Arg1339Gln	missense	Exon 27 of 30	NP_001371381.1
	SORBS1	NM_001384448.1		c.3989G>A	p.Arg1330Gln	missense	Exon 26 of 29	NP_001371377.1	A0A3B3IRW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORBS1	ENST00000371247.7	TSL:5 MANE Select	c.3140G>A	p.Arg1047Gln	missense	Exon 30 of 33	ENSP00000360293.2	Q9BX66-1
	SORBS1	ENST00000361941.7	TSL:1	c.3140G>A	p.Arg1047Gln	missense	Exon 28 of 31	ENSP00000355136.3	Q9BX66-1
	SORBS1	ENST00000371227.8	TSL:1	c.3002G>A	p.Arg1001Gln	missense	Exon 28 of 32	ENSP00000360271.3	Q9BX66-11

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000459 AC: 10 AN: 218010 AF XY: 0.0000259

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000190

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000203

Gnomad OTH exome AF: 0.000190

GnomAD4 exome AF: 0.0000120 AC: 17 AN: 1417296 Hom.: 0 Cov.: 32 AF XY: 0.00000716 AC XY: 5 AN XY: 698314

African (AFR) AF: 0.00 AC: 0 AN: 32516

American (AMR) AF: 0.000168 AC: 7 AN: 41574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23338

East Asian (EAS) AF: 0.00 AC: 0 AN: 39170

South Asian (SAS) AF: 0.00 AC: 0 AN: 78690

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.00000828 AC: 9 AN: 1086302

Other (OTH) AF: 0.00 AC: 0 AN: 58404

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74264

African (AFR) AF: 0.00 AC: 0 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000413 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.42
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.0090
Sift	Uncertain	0.017	D
Sift4G	Benign	0.34	T
Polyphen		0.49	P
Vest4		0.19
MutPred		0.26		Loss of glycosylation at P1046 (P = 0.062)
MVP		0.36
MPC		0.24
ClinPred		0.035	T
GERP RS		-1.7
PromoterAI		-0.015	Neutral
Varity_R		0.043
gMVP		0.22
Mutation Taster		=99/1	polymorphism

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: rs193920900; hg19: chr10-97096777;