chr1-248813105-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_030645.3(SH3BP5L):​c.595C>T​(p.Arg199Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000783 in 1,611,272 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (1 hom.)
• Consequence: SH3BP5L NM_030645.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3080204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP5L	NM_030645.3	c.595C>T	p.Arg199Trp	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>T	p.Arg199Trp	missense_variant	Exon 6 of 7	1	NM_030645.3	ENSP00000355428.5
SH3BP5L	ENST00000475978.1	n.2087C>T		non_coding_transcript_exon_variant	Exon 8 of 9	2
SH3BP5L	ENST00000484202.2	n.1069C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.000507 AC: 77 AN: 151900 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000927

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000515 AC: 128 AN: 248356 AF XY: 0.000543

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.00101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000954

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000812 AC: 1185 AN: 1459254 Hom.: 1 Cov.: 31 AF XY: 0.000795 AC XY: 577 AN XY: 725768

African (AFR) AF: 0.000239 AC: 8 AN: 33440

American (AMR) AF: 0.0000449 AC: 2 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26060

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39588

South Asian (SAS) AF: 0.0000698 AC: 6 AN: 85966

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

Middle Eastern (MID) AF: 0.000539 AC: 3 AN: 5570

European-Non Finnish (NFE) AF: 0.000987 AC: 1096 AN: 1110580

Other (OTH) AF: 0.000631 AC: 38 AN: 60250

GnomAD4 genome AF: 0.000507 AC: 77 AN: 152018 Hom.: 0 Cov.: 33 AF XY: 0.000377 AC XY: 28 AN XY: 74310

African (AFR) AF: 0.000217 AC: 9 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000927 AC: 63 AN: 67966

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

Alfa AF: 0.000875 Hom.: 0

Bravo AF: 0.000476

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.000932

EpiControl AF: 0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.595C>T (p.R199W) alteration is located in exon 6 (coding exon 5) of the SH3BP5L gene. This alteration results from a C to T substitution at nucleotide position 595, causing the arginine (R) at amino acid position 199 to be replaced by a tryptophan (W). 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	0.20
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.010
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.39	N
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.083	D
MutationAssessor	Benign	1.7	L
PhyloP100		1.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.57
MVP		0.49
MPC		1.3
ClinPred		0.065	T
GERP RS		0.42
Varity_R		0.16
gMVP		0.29
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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;