19-4362644-C-T

Variant names:

• chr19-4362644-C-T
• rs1972653630
• NM_003025.4:c.821G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_003025.4(SH3GL1):​c.821G>A​(p.Gly274Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SH3GL1 NM_003025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.41

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3GL1	NM_003025.4	c.821G>A	p.Gly274Asp	missense_variant	Exon 8 of 10	ENST00000269886.7	NP_003016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3GL1	ENST00000269886.7	c.821G>A	p.Gly274Asp	missense_variant	Exon 8 of 10	1	NM_003025.4	ENSP00000269886.2
SH3GL1	ENST00000417295.6	c.677G>A	p.Gly226Asp	missense_variant	Exon 7 of 9	2		ENSP00000404568.2
SH3GL1	ENST00000598564.5	c.629G>A	p.Gly210Asp	missense_variant	Exon 8 of 10	2		ENSP00000470792.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461500 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.821G>A (p.G274D) alteration is located in exon 8 (coding exon 8) of the SH3GL1 gene. This alteration results from a G to A substitution at nucleotide position 821, causing the glycine (G) at amino acid position 274 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Benign	0.13
Sift	Benign	0.16	T;.;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.93	P;.;.
Vest4		0.75
MutPred		0.20		Loss of glycosylation at S271 (P = 0.1001);.;.;
MVP		0.56
MPC		0.64
ClinPred		0.93	D
GERP RS		3.8
Varity_R		0.30
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs1972653630; hg19: chr19-4362641;