9-129012244-C-A

Variant names:

• chr9-129012244-C-A
• rs751054150
• NM_020145.4:c.616G>T

Variant summary

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

The NM_020145.4(SH3GLB2):​c.616G>T​(p.Ala206Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000876 in 1,141,706 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A206T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: SH3GLB2 NM_020145.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.90
• 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 2 ACMG points.

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

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.616G>T	p.Ala206Ser	missense	Exon 6 of 11	NP_064530.1	Q9NR46-1
	SH3GLB2	NM_001438434.1		c.616G>T	p.Ala206Ser	missense	Exon 6 of 11	NP_001425363.1
	SH3GLB2	NM_001369913.1		c.661G>T	p.Ala221Ser	missense	Exon 7 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.616G>T	p.Ala206Ser	missense	Exon 6 of 11	ENSP00000361645.3	Q9NR46-1
	SH3GLB2	ENST00000372554.8	TSL:1	c.628G>T	p.Ala210Ser	missense	Exon 7 of 13	ENSP00000361634.4	Q9NR46-2
	SH3GLB2	ENST00000372559.5	TSL:1	c.616G>T	p.Ala206Ser	missense	Exon 6 of 12	ENSP00000361640.1	Q9NR46-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.76e-7 AC: 1 AN: 1141706 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 544134

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

African (AFR) AF: 0.00 AC: 0 AN: 24608

American (AMR) AF: 0.00 AC: 0 AN: 11252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14936

East Asian (EAS) AF: 0.00 AC: 0 AN: 29192

South Asian (SAS) AF: 0.00 AC: 0 AN: 26922

European-Finnish (FIN) AF: 0.0000259 AC: 1 AN: 38598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4590

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 945718

Other (OTH) AF: 0.00 AC: 0 AN: 45890

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.22
Sift	Benign	0.25	T
Sift4G	Benign	0.43	T
Polyphen		0.66	P
Vest4		0.60
MutPred		0.60		Gain of disorder (P = 0.0473)
MVP		0.36
MPC		0.91
ClinPred		0.83	D
GERP RS		5.8
Varity_R		0.11
gMVP		0.35
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs751054150; hg19: chr9-131774523;