10-95346408-T-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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.

• 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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORBS1	NM_001034954.3	c.2427A>G	p.Leu809Leu	splice_region_variant, synonymous_variant	Exon 26 of 33	ENST00000371247.7	NP_001030126.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORBS1	ENST00000371247.7	c.2427A>G	p.Leu809Leu	splice_region_variant, synonymous_variant	Exon 26 of 33	5	NM_001034954.3	ENSP00000360293.2

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

GnomAD3 exomes AF: 0.364 AC: 90778 AN: 249406 Hom.: 18825 AF XY: 0.365 AC XY: 49174 AN XY: 134688

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 SAS exome AF: 0.475

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

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.492

Gnomad4 ASJ exome AF: 0.354

Gnomad4 EAS exome AF: 0.704

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.294

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.319

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

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.385

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.675

Gnomad4 SAS AF: 0.490

Gnomad4 FIN AF: 0.304

Gnomad4 NFE AF: 0.277

Gnomad4 OTH AF: 0.333

Alfa AF: 0.295 Hom.: 17002

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.0
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.014
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

Publications

LitVar

Other links and lift over

dbSNP: rs726176; hg19: chr10-97106165; COSMIC: COSV53358251;