rs755032679

Variant names:

• chr19-4361713-C-A
• rs755032679
• NM_003025.4:c.994G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-4361713-C-A
• chr19-4361713-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003025.4(SH3GL1):​c.994G>T​(p.Val332Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. V332I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SH3GL1 NM_003025.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• Publications: 0 publications found

Genes affected

SH3GL1 (HGNC:10830): (SH3 domain containing GRB2 like 1, endophilin A2) This gene encodes a member of the endophilin family of Src homology 3 domain-containing proteins. The encoded protein is involved in endocytosis and may also play a role in the cell cycle. Overexpression of this gene may play a role in leukemogenesis, and the encoded protein has been implicated in acute myeloid leukemia as a fusion partner of the myeloid-lymphoid leukemia protein. Pseudogenes of this gene are located on the long arm of chromosomes 11 and 17. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

SH3GL1 Gene-Disease associations (from GenCC):

• immunodeficiency disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3616245).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003025.4. 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
	SH3GL1	NM_003025.4	MANE Select	c.994G>T	p.Val332Phe	missense	Exon 10 of 10	NP_003016.1	Q6FGM0
	SH3GL1	NM_001199943.2		c.850G>T	p.Val284Phe	missense	Exon 9 of 9	NP_001186872.1	Q99961-2
	SH3GL1	NM_001199944.2		c.802G>T	p.Val268Phe	missense	Exon 10 of 10	NP_001186873.1	Q99961-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3GL1	ENST00000269886.7	TSL:1 MANE Select	c.994G>T	p.Val332Phe	missense	Exon 10 of 10	ENSP00000269886.2	Q99961-1
	SH3GL1	ENST00000908568.1		c.991G>T	p.Val331Phe	missense	Exon 10 of 10	ENSP00000578627.1
	SH3GL1	ENST00000945946.1		c.955G>T	p.Val319Phe	missense	Exon 10 of 10	ENSP00000616005.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460948 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726880

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52770

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.3
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.019	D
Polyphen		0.67	P
Vest4		0.27
MutPred		0.52		Gain of disorder (P = 0.222)
MVP		0.73
MPC		1.2
ClinPred		0.79	D
GERP RS		-4.7
Varity_R		0.41
gMVP		0.58
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs755032679; hg19: chr19-4361710;