10-95346408-T-C

Variant names:

• chr10-95346408-T-C
• rs726176
• NM_001034954.3:c.2427A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001034954.3(SORBS1):​c.2427A>G​(p.Leu809Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,600,732 control chromosomes in the GnomAD database, including 81,552 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L809L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (7281 hom., cov: 32)
  • Exomes 𝑓: 0.30 (74271 hom.)
• Consequence: SORBS1 NM_001034954.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001502
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP7: Synonymous conserved (PhyloP=0.049 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

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.2427A>G	p.Leu809Leu	splice_region synonymous	Exon 26 of 33	NP_001030126.2	Q9BX66-1
	SORBS1	NM_001384452.1		c.3303A>G	p.Leu1101Leu	splice_region synonymous	Exon 23 of 30	NP_001371381.1
	SORBS1	NM_001384448.1		c.3276A>G	p.Leu1092Leu	splice_region synonymous	Exon 22 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.2427A>G	p.Leu809Leu	splice_region synonymous	Exon 26 of 33	ENSP00000360293.2	Q9BX66-1
	SORBS1	ENST00000361941.7	TSL:1	c.2427A>G	p.Leu809Leu	splice_region synonymous	Exon 24 of 31	ENSP00000355136.3	Q9BX66-1
	SORBS1	ENST00000371227.8	TSL:1	c.2289A>G	p.Leu763Leu	splice_region synonymous	Exon 24 of 32	ENSP00000360271.3	Q9BX66-11

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44617 AN: 152006 Hom.: 7275 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.330

GnomAD2 exomes AF: 0.364 AC: 90778 AN: 249406 AF XY: 0.365

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.670

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.279

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.304 AC: 439806 AN: 1448606 Hom.: 74271 Cov.: 29 AF XY: 0.310 AC XY: 223269 AN XY: 721336

African (AFR) AF: 0.210 AC: 6970 AN: 33218

American (AMR) AF: 0.492 AC: 21795 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 9208 AN: 26022

East Asian (EAS) AF: 0.704 AC: 27849 AN: 39564

South Asian (SAS) AF: 0.475 AC: 40527 AN: 85256

European-Finnish (FIN) AF: 0.294 AC: 15694 AN: 53332

Middle Eastern (MID) AF: 0.353 AC: 2019 AN: 5712

European-Non Finnish (NFE) AF: 0.269 AC: 296629 AN: 1101274

Other (OTH) AF: 0.319 AC: 19115 AN: 59898

GnomAD4 genome AF: 0.294 AC: 44663 AN: 152126 Hom.: 7281 Cov.: 32 AF XY: 0.303 AC XY: 22497 AN XY: 74364

African (AFR) AF: 0.209 AC: 8678 AN: 41502

American (AMR) AF: 0.385 AC: 5880 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1210 AN: 3470

East Asian (EAS) AF: 0.675 AC: 3497 AN: 5180

South Asian (SAS) AF: 0.490 AC: 2361 AN: 4820

European-Finnish (FIN) AF: 0.304 AC: 3217 AN: 10568

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18807 AN: 67978

Other (OTH) AF: 0.333 AC: 705 AN: 2116

Alfa AF: 0.293 Hom.: 33561

Bravo AF: 0.300

Asia WGS AF: 0.552 AC: 1917 AN: 3478

EpiCase AF: 0.298

EpiControl AF: 0.291

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.0
DANN	Benign	0.75
PhyloP100		0.049
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.014
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs726176; hg19: chr10-97106165; COSMIC: COSV53358251;