chr1-248813053-C-T

Variant names:

• chr1-248813053-C-T
• rs147847671
• NM_030645.3:c.647G>A

Variant summary

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

The NM_030645.3(SH3BP5L):​c.647G>A​(p.Arg216Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000825 in 1,611,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: SH3BP5L NM_030645.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81
• Publications: 4 publications found

Genes affected

SH3BP5L (HGNC:29360): (SH3 binding domain protein 5 like) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in intracellular signal transduction and negative regulation of protein tyrosine kinase activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2665129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP5L	NM_030645.3	c.647G>A	p.Arg216Gln	missense_variant	Exon 6 of 7	ENST00000366472.6	NP_085148.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP5L	ENST00000366472.6	c.647G>A	p.Arg216Gln	missense_variant	Exon 6 of 7	1	NM_030645.3	ENSP00000355428.5
SH3BP5L	ENST00000475978.1	n.2139G>A		non_coding_transcript_exon_variant	Exon 8 of 9	2
SH3BP5L	ENST00000484202.2	n.1121G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000601 AC: 15 AN: 249520 AF XY: 0.0000445

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000888

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000870 AC: 127 AN: 1459340 Hom.: 0 Cov.: 31 AF XY: 0.0000744 AC XY: 54 AN XY: 725676

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39590

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.000107 AC: 119 AN: 1110290

Other (OTH) AF: 0.0000664 AC: 4 AN: 60242

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74492

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.647G>A (p.R216Q) alteration is located in exon 6 (coding exon 5) of the SH3BP5L gene. This alteration results from a G to A substitution at nucleotide position 647, causing the arginine (R) at amino acid position 216 to be replaced by a glutamine (Q). 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	Benign	0.34
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.65	N
PhyloP100		2.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.25
Sift	Benign	0.031	D
Sift4G	Benign	0.080	T
Polyphen		0.96	D
Vest4		0.48
MVP		0.41
MPC		0.84
ClinPred		0.15	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.28
Mutation Taster		=96/4	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: rs147847671; hg19: chr1-249107252;