chr1-248813126-G-A

Variant names:

• chr1-248813126-G-A
• rs554983579
• NM_030645.3:c.574C>T

Variant summary

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

The NM_030645.3(SH3BP5L):​c.574C>T​(p.Arg192Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,606,994 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. R192G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SH3BP5L NM_030645.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 1 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP5L	NM_030645.3	c.574C>T	p.Arg192Trp	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.574C>T	p.Arg192Trp	missense_variant	Exon 6 of 7	1	NM_030645.3	ENSP00000355428.5
SH3BP5L	ENST00000475978.1	n.2066C>T		non_coding_transcript_exon_variant	Exon 8 of 9	2
SH3BP5L	ENST00000484202.2	n.1048C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151768 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000205 AC: 5 AN: 243556 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.000307

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1455106 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 723436

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.0000678 AC: 3 AN: 44238

Ashkenazi Jewish (ASJ) AF: 0.000193 AC: 5 AN: 25870

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39424

South Asian (SAS) AF: 0.00 AC: 0 AN: 85478

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5348

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1108466

Other (OTH) AF: 0.0000333 AC: 2 AN: 60028

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151888 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74238

African (AFR) AF: 0.0000483 AC: 2 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000551

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.041
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.43
Sift	Benign	0.085	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.67
MutPred		0.43		Loss of disorder (P = 0.014);
MVP		0.50
MPC		1.3
ClinPred		0.78	D
GERP RS		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.11
gMVP		0.39
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: -36

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs554983579; hg19: chr1-249107325; COSMIC: COSV107458678; COSMIC: COSV107458678;