9-129014812-G-T

Variant names:

• chr9-129014812-G-T
• rs1407669751
• NM_020145.4:c.427C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020145.4(SH3GLB2):​c.427C>A​(p.Pro143Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,802 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: SH3GLB2 NM_020145.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.56
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

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.427C>A	p.Pro143Thr	missense	Exon 4 of 11	NP_064530.1	Q9NR46-1
	SH3GLB2	NM_001438434.1		c.427C>A	p.Pro143Thr	missense	Exon 4 of 11	NP_001425363.1
	SH3GLB2	NM_001369913.1		c.460C>A	p.Pro154Thr	missense	Exon 4 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.427C>A	p.Pro143Thr	missense	Exon 4 of 11	ENSP00000361645.3	Q9NR46-1
	SH3GLB2	ENST00000372554.8	TSL:1	c.427C>A	p.Pro143Thr	missense	Exon 4 of 13	ENSP00000361634.4	Q9NR46-2
	SH3GLB2	ENST00000372559.5	TSL:1	c.427C>A	p.Pro143Thr	missense	Exon 4 of 12	ENSP00000361640.1	Q9NR46-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44714

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60390

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	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.92		Gain of catalytic residue at P143 (P = 0.0508)
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.73
Mutation Taster		=66/34	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: rs1407669751; hg19: chr9-131777091;