chr10-95318384-C-G

Variant names:

• chr10-95318384-C-G
• rs756605275
• NM_001034954.3:c.3747G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001034954.3(SORBS1):​c.3747G>C​(p.Glu1249Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E1249E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SORBS1 NM_001034954.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

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.3747G>C	p.Glu1249Asp	missense	Exon 32 of 33	NP_001030126.2	Q9BX66-1
	SORBS1	NM_001384452.1		c.4755G>C	p.Glu1585Asp	missense	Exon 29 of 30	NP_001371381.1
	SORBS1	NM_001384448.1		c.4728G>C	p.Glu1576Asp	missense	Exon 28 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.3747G>C	p.Glu1249Asp	missense	Exon 32 of 33	ENSP00000360293.2	Q9BX66-1
	SORBS1	ENST00000361941.7	TSL:1	c.3747G>C	p.Glu1249Asp	missense	Exon 30 of 31	ENSP00000355136.3	Q9BX66-1
	SORBS1	ENST00000371227.8	TSL:1	c.3669G>C	p.Glu1223Asp	missense	Exon 31 of 32	ENSP00000360271.3	Q9BX66-11

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245388 AF XY: 0.00000754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.094
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.79		Gain of disorder (P = 0.2277)
MVP		0.79
MPC		0.71
ClinPred		0.95	D
GERP RS		1.9
Varity_R		0.47
gMVP		0.74
Mutation Taster		=63/37	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: rs756605275; hg19: chr10-97078141;