3-15259025-A-C

Variant names:

• chr3-15259025-A-C
• rs774575202
• NM_004844.5:c.695T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004844.5(SH3BP5):​c.695T>G​(p.Leu232Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SH3BP5 NM_004844.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.81
• Publications: 1 publications found

Genes affected

SH3BP5 (HGNC:10827): (SH3 domain binding protein 5) Enables guanyl-nucleotide exchange factor activity and protein kinase inhibitor activity. Acts upstream of or within intracellular signal transduction. Located in cytoplasmic vesicle membrane and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

SH3BP5-AS1 (HGNC:44501): (SH3BP5 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004844.5. 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
	SH3BP5	NM_004844.5	MANE Select	c.695T>G	p.Leu232Arg	missense	Exon 7 of 9	NP_004835.2	O60239-1
	SH3BP5	NM_001018009.4		c.224T>G	p.Leu75Arg	missense	Exon 7 of 9	NP_001018009.2	O60239-2
	SH3BP5-AS1	NR_046084.1		n.3815A>C		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP5	ENST00000383791.8	TSL:1 MANE Select	c.695T>G	p.Leu232Arg	missense	Exon 7 of 9	ENSP00000373301.3	O60239-1
	SH3BP5	ENST00000408919.7	TSL:1	c.224T>G	p.Leu75Arg	missense	Exon 7 of 9	ENSP00000386231.3	O60239-2
	SH3BP5-AS1	ENST00000420195.1	TSL:1	n.3815A>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.31
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.072
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.55	N
PhyloP100		5.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.30
Sift	Benign	0.076	T
Sift4G	Benign	0.53	T
Polyphen		0.0020	B
Vest4		0.45
MutPred		0.78		Gain of MoRF binding (P = 0.023)
MVP		0.88
MPC		0.11
ClinPred		0.87	D
GERP RS		5.4
Varity_R		0.72
gMVP		0.80
Mutation Taster		=31/69	disease causing

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: rs774575202; hg19: chr3-15300532;