chr1-248813105-G-C

Variant names:

• chr1-248813105-G-C
• rs149049712
• NM_030645.3:c.595C>G

Variant summary

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

The NM_030645.3(SH3BP5L):​c.595C>G​(p.Arg199Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. R199W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SH3BP5L NM_030645.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• Publications: 0 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=0.4096168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP5L	NM_030645.3	c.595C>G	p.Arg199Gly	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.595C>G	p.Arg199Gly	missense_variant	Exon 6 of 7	1	NM_030645.3	ENSP00000355428.5
SH3BP5L	ENST00000475978.1	n.2087C>G		non_coding_transcript_exon_variant	Exon 8 of 9	2
SH3BP5L	ENST00000484202.2	n.1069C>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459256 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725768

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 85966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110580

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.41
Sift	Benign	0.19	T
Sift4G	Benign	0.38	T
Polyphen		0.68	P
Vest4		0.60
MutPred		0.49		Loss of MoRF binding (P = 0.0152);
MVP		0.29
MPC		0.92
ClinPred		0.85	D
GERP RS		0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.20
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs149049712; hg19: chr1-249107304;