Variant 2-235041274-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014521.3(SH3BP4):c.505C>T(p.Pro169Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P169A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SH3BP4
NM_014521.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.66

Variant links:

Genes affected

SH3BP4 (HGNC:10826): (SH3 domain binding protein 4) This gene encodes a protein with 3 Asn-Pro-Phe (NPF) motifs, an SH3 domain, a PXXP motif, a bipartite nuclear targeting signal, and a tyrosine phosphorylation site. This protein is involved in cargo-specific control of clathrin-mediated endocytosis, specifically controlling the internalization of a specific protein receptor. [provided by RefSeq, Jul 2008]

SH3BP4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP4	NM_014521.3 linkuse as main transcript	c.505C>T	p.Pro169Ser	missense_variant	4/6	ENST00000392011.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP4	ENST00000392011.7 linkuse as main transcript	c.505C>T	p.Pro169Ser	missense_variant	4/6	1	NM_014521.3	P1	Q9P0V3-1
SH3BP4	ENST00000344528.8 linkuse as main transcript	c.505C>T	p.Pro169Ser	missense_variant	4/6	1		P1	Q9P0V3-1
SH3BP4	ENST00000409212.5 linkuse as main transcript	c.505C>T	p.Pro169Ser	missense_variant	4/6	5		P1	Q9P0V3-1
SH3BP4	ENST00000446904.5 linkuse as main transcript	c.505C>T	p.Pro169Ser	missense_variant	4/4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.505C>T (p.P169S) alteration is located in exon 4 (coding exon 2) of the SH3BP4 gene. This alteration results from a C to T substitution at nucleotide position 505, causing the proline (P) at amino acid position 169 to be replaced by a serine (S). 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

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T;T;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Benign

-0.68

MutationAssessor

Pathogenic

3.0

M;M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.6

D;D;D;N

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.76

MutPred

0.56

Loss of catalytic residue at P169 (P = 0.1062);Loss of catalytic residue at P169 (P = 0.1062);Loss of catalytic residue at P169 (P = 0.1062);Loss of catalytic residue at P169 (P = 0.1062);

MVP

0.75

MPC

0.92

ClinPred

0.96

GERP RS

5.6

Varity_R

0.44

gMVP

0.72

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over