8-22554598-G-A

Variant names:

• chr8-22554598-G-A
• rs370407437
• NM_005775.5:c.92G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005775.5(SORBS3):​c.92G>A​(p.Arg31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000823 in 1,611,784 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R31P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (18 hom.)
• Consequence: SORBS3 NM_005775.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 2 publications found

Genes affected

SORBS3 (HGNC:30907): (sorbin and SH3 domain containing 3) This gene encodes an SH3 domain-containing adaptor protein. The presence of SH3 domains play a role in this protein's ability to bind other cytoplasmic molecules and contribute to cystoskeletal organization, cell adhesion and migration, signaling, and gene expression. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056011677).
• BS2: High Homozygotes in GnomAdExome4 at 18 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005775.5. 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
	SORBS3	NM_005775.5	MANE Select	c.92G>A	p.Arg31Gln	missense	Exon 2 of 21	NP_005766.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORBS3	ENST00000240123.12	TSL:1 MANE Select	c.92G>A	p.Arg31Gln	missense	Exon 2 of 21	ENSP00000240123.7	O60504-1
	SORBS3	ENST00000897780.1		c.92G>A	p.Arg31Gln	missense	Exon 2 of 21	ENSP00000567839.1
	SORBS3	ENST00000897778.1		c.92G>A	p.Arg31Gln	missense	Exon 2 of 21	ENSP00000567837.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00768

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00183 AC: 452 AN: 247038 AF XY: 0.00249

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.000879 AC: 1283 AN: 1459460 Hom.: 18 Cov.: 31 AF XY: 0.00128 AC XY: 926 AN XY: 726106

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0139 AC: 1194 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111750

Other (OTH) AF: 0.000945 AC: 57 AN: 60342

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74488

African (AFR) AF: 0.0000962 AC: 4 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00748 AC: 36 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000812 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00209 AC: 254

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.1
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.012
Sift	Benign	0.32	T
Sift4G	Benign	0.63	T
Polyphen		0.012	B
Vest4		0.19
MVP		0.18
MPC		0.13
ClinPred		0.014	T
GERP RS		-1.5
PromoterAI		-0.057	Neutral
Varity_R		0.034
gMVP		0.20
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: rs370407437; hg19: chr8-22412111;