2-230044-C-T

Variant names:

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

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>A​(p.Ala235Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,441,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: SH3YL1 NM_015677.4 missense, splice_region
• Scores: Splicing: ADA: 0.01451
• Clinical Significance: Not reported in ClinVar
• 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=0.11699259).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3YL1	NM_015677.4	c.703G>A	p.Ala235Thr	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>A	p.Ala235Thr	missense_variant, splice_region_variant	Exon 8 of 10	1	NM_015677.4	ENSP00000348471.5
SH3YL1	ENST00000626873.2	c.415G>A	p.Ala139Thr	missense_variant, splice_region_variant	Exon 11 of 13	5		ENSP00000485824.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1441872 Hom.: 0 Cov.: 29 AF XY: 0.00000559 AC XY: 4 AN XY: 716028

Gnomad4 AFR exome AF: 0.0000306

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: 0.0000840

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.088	.;.;.;T;T;.;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.76	T;T;.;.;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.;L;L;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.45	N;.;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.29	T;.;T;T;T;T;T;T
Sift4G	Benign	0.58	.;T;T;.;.;T;T;T
Polyphen		0.0060	B;B;B;B;B;B;.;.
Vest4		0.23
MutPred		0.25		Gain of phosphorylation at A235 (P = 0.0078);.;.;Gain of phosphorylation at A235 (P = 0.0078);Gain of phosphorylation at A235 (P = 0.0078);.;.;.;
MVP		0.27
MPC		0.077
ClinPred		0.16	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.030		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; COSMIC: COSV62155436; COSMIC: COSV62155436;