Genetic Variant NM_015677.4:c.703G>C (chr2-230044-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015677.4(SH3YL1):c.703G>C(p.Ala235Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SH3YL1
NM_015677.4 missense, splice_region

Scores

Splicing: ADA: 0.4700

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05

Variant links:

Genes affected

SH3YL1 (HGNC:29546): (SH3 and SYLF domain containing 1) Enables phosphatase binding activity and phosphatidylinositol binding activity. Predicted to act upstream of or within phosphatidylinositol biosynthetic process and regulation of ruffle assembly. Located in ruffle membrane. [provided by Alliance of Genome Resources, Apr 2022]

SH3YL1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16330743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3YL1	NM_015677.4 link	c.703G>C	p.Ala235Pro	missense_variant, splice_region_variant	Exon 8 of 10	ENST00000356150.10	NP_056492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3YL1	ENST00000356150.10 link	c.703G>C	p.Ala235Pro	missense_variant, splice_region_variant	Exon 8 of 10	1	NM_015677.4	ENSP00000348471.5		Q96HL8-1
SH3YL1	ENST00000626873.2 link	c.415G>C	p.Ala139Pro	missense_variant, splice_region_variant	Exon 11 of 13	5		ENSP00000485824.1		Q96HL8-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1441872

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716028

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:

0.00

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

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.703G>C (p.A235P) alteration is located in exon 8 (coding exon 8) of the SH3YL1 gene. This alteration results from a G to C substitution at nucleotide position 703, causing the alanine (A) at amino acid position 235 to be replaced by a proline (P). 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

0.079

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

.;.;.;T;T;.;T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.73

T;T;.;.;T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.16

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.;.;L;L;.;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.55

N;.;N;N;N;N;N;N

REVEL

Benign

0.076

Sift

Benign

0.14

T;.;T;T;T;T;T;T

Sift4G

Benign

0.29

.;T;T;.;.;T;T;T

Polyphen

0.0010

B;D;B;B;B;B;.;.

Vest4

0.17

MutPred

0.33

Gain of glycosylation at A235 (P = 0.0087);.;.;Gain of glycosylation at A235 (P = 0.0087);Gain of glycosylation at A235 (P = 0.0087);.;.;.;

MVP

0.40

MPC

0.10

ClinPred

0.17

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.47

dbscSNV1_RF

Benign

0.49

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over