10-95432567-A-G

Variant names:

• chr10-95432567-A-G
• rs943542
• NM_001034954.3:c.182T>C

Variant summary

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

The NM_001034954.3(SORBS1):​c.182T>C​(p.Leu61Pro) variant causes a missense change. The variant allele was found at a frequency of 0.996 in 1,613,234 control chromosomes in the GnomAD database, including 800,802 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.98 (73365 hom., cov: 30)
  • Exomes 𝑓: 1.0 (727437 hom.)
• Consequence: SORBS1 NM_001034954.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.66

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=6.8947134E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORBS1	NM_001034954.3	c.182T>C	p.Leu61Pro	missense_variant	Exon 6 of 33	ENST00000371247.7	NP_001030126.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORBS1	ENST00000371247.7	c.182T>C	p.Leu61Pro	missense_variant	Exon 6 of 33	5	NM_001034954.3	ENSP00000360293.2

Frequencies

GnomAD3 genomes AF: 0.982 AC: 149227 AN: 152006 Hom.: 73310 Cov.: 30

Gnomad AFR AF: 0.938

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.978

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.980

GnomAD3 exomes AF: 0.995 AC: 249277 AN: 250542 Hom.: 124036 AF XY: 0.996 AC XY: 134866 AN XY: 135398

Gnomad AFR exome AF: 0.937

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.998 AC: 1457920 AN: 1461110 Hom.: 727437 Cov.: 38 AF XY: 0.998 AC XY: 725408 AN XY: 726822

Gnomad4 AFR exome AF: 0.937

Gnomad4 AMR exome AF: 0.995

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.995

GnomAD4 genome AF: 0.982 AC: 149341 AN: 152124 Hom.: 73365 Cov.: 30 AF XY: 0.982 AC XY: 73037 AN XY: 74358

Gnomad4 AFR AF: 0.938

Gnomad4 AMR AF: 0.991

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.981

Alfa AF: 0.996 Hom.: 151205

Bravo AF: 0.979

TwinsUK AF: 0.999 AC: 3705

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.942 AC: 4151

ESP6500EA AF: 1.00 AC: 8597

ExAC AF: 0.994 AC: 120652

Asia WGS AF: 0.995 AC: 3462 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.034
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.31
DEOGEN2	Benign	0.047	.;.;.;.;T;.;T;.;.;.;.;.;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.44	T;T;T;T;T;T;.;.;T;T;T;T;T
MetaRNN	Benign	6.9e-7	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.1	N;.;N;N;N;.;N;N;N;.;N;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	5.9	N;N;N;N;N;.;N;N;N;N;N;N;.
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;T;T;T;.;T;T;T;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0	B;B;B;B;B;.;B;B;B;B;.;B;.
Vest4		0.16
MPC		0.30
ClinPred		0.0047	T
GERP RS		5.8
Varity_R		0.099
gMVP		0.081

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: rs943542; hg19: chr10-97192324;