4-185615127-T-A

Variant names:

• chr4-185615127-T-A
• rs1406179391
• NM_001395207.1:c.3272A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001395207.1(SORBS2):​c.3272A>T​(p.Tyr1091Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,412 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SORBS2 NM_001395207.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00
• Publications: 0 publications found

Genes affected

SORBS2 (HGNC:24098): (sorbin and SH3 domain containing 2) Arg and c-Abl represent the mammalian members of the Abelson family of non-receptor protein-tyrosine kinases. They interact with the Arg/Abl binding proteins via the SH3 domains present in the carboxy end of the latter group of proteins. This gene encodes the sorbin and SH3 domain containing 2 protein. It has three C-terminal SH3 domains and an N-terminal sorbin homology (SoHo) domain that interacts with lipid raft proteins. The subcellular localization of this protein in epithelial and cardiac muscle cells suggests that it functions as an adapter protein to assemble signaling complexes in stress fibers, and that it is a potential link between Abl family kinases and the actin cytoskeleton. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

SORBS2 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395207.1. 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
	SORBS2	NM_001395207.1	MANE Select	c.3272A>T	p.Tyr1091Phe	missense	Exon 22 of 27	NP_001382136.1	A0A8Q3WKK4
	SORBS2	NM_001394245.1		c.3230A>T	p.Tyr1077Phe	missense	Exon 20 of 25	NP_001381174.1
	SORBS2	NM_001394246.1		c.3173A>T	p.Tyr1058Phe	missense	Exon 19 of 24	NP_001381175.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORBS2	ENST00000695409.1	MANE Select	c.3272A>T	p.Tyr1091Phe	missense	Exon 22 of 27	ENSP00000511888.1	A0A8Q3WKK4
	SORBS2	ENST00000284776.11	TSL:1	c.2672A>T	p.Tyr891Phe	missense	Exon 16 of 21	ENSP00000284776.7	O94875-1
	SORBS2	ENST00000437304.6	TSL:1	c.1844A>T	p.Tyr615Phe	missense	Exon 18 of 23	ENSP00000396008.2	O94875-10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251464 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460412 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726652

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110688

Other (OTH) AF: 0.00 AC: 0 AN: 60342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.55	N
PhyloP100		8.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.34
Sift	Benign	0.043	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.42
MutPred		0.46		Loss of phosphorylation at Y891 (P = 0.0561)
MVP		0.50
MPC		0.41
ClinPred		0.80	D
GERP RS		6.2
Varity_R		0.50
gMVP		0.31
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1406179391; hg19: chr4-186536281;