NM_020145.4:c.749T>C

Variant names:

• chr9-129009861-A-G
• NM_020145.4:c.749T>C

Variant summary

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

The NM_020145.4(SH3GLB2):​c.749T>C​(p.Leu250Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L250V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SH3GLB2 NM_020145.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.91
• Publications: 0 publications found

Genes affected

SH3GLB2 (HGNC:10834): (SH3 domain containing GRB2 like, endophilin B2) Enables identical protein binding activity. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.907

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020145.4. 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
	SH3GLB2	NM_020145.4	MANE Select	c.749T>C	p.Leu250Pro	missense	Exon 9 of 11	NP_064530.1	Q9NR46-1
	SH3GLB2	NM_001438434.1		c.821T>C	p.Leu274Pro	missense	Exon 9 of 11	NP_001425363.1
	SH3GLB2	NM_001369913.1		c.794T>C	p.Leu265Pro	missense	Exon 10 of 13	NP_001356842.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3GLB2	ENST00000372564.8	TSL:1 MANE Select	c.749T>C	p.Leu250Pro	missense	Exon 9 of 11	ENSP00000361645.3	Q9NR46-1
	SH3GLB2	ENST00000372554.8	TSL:1	c.761T>C	p.Leu254Pro	missense	Exon 10 of 13	ENSP00000361634.4	Q9NR46-2
	SH3GLB2	ENST00000372559.5	TSL:1	c.749T>C	p.Leu250Pro	missense	Exon 9 of 12	ENSP00000361640.1	Q9NR46-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.035	D
Polyphen		0.45	B
Vest4		0.82
MutPred		0.85		Loss of stability (P = 0.0304)
MVP		0.72
MPC		0.51
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.88
gMVP		0.90
Mutation Taster		=25/75	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

hg19: chr9-131772140;