2-230044-C-G

Variant names:

• chr2-230044-C-G
• rs371041609
• NM_015677.4:c.703G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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

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]

ACMG classification

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	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	c.703G>C	p.Ala235Pro	missense_variant, splice_region_variant	Exon 8 of 10	1	NM_015677.4	ENSP00000348471.5
SH3YL1	ENST00000626873.2	c.415G>C	p.Ala139Pro	missense_variant, splice_region_variant	Exon 11 of 13	5		ENSP00000485824.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441872 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
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	D
LIST_S2	Benign	0.73	T;T;.;.;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.;L;L;.;.;.
PrimateAI	Benign	0.36	T
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	T
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

Other links and lift over

dbSNP: rs371041609; hg19: chr2-230044;