chr2-233183-T-G

Position:

• chr2-233183-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015677.4(SH3YL1):​c.451A>C​(p.Thr151Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,443,436 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SH3YL1 NM_015677.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.10

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3YL1	NM_015677.4	c.451A>C	p.Thr151Pro	missense_variant	6/10	ENST00000356150.10	NP_056492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3YL1	ENST00000356150.10	c.451A>C	p.Thr151Pro	missense_variant	6/10	1	NM_015677.4	ENSP00000348471	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443436 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 718242

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: 0.0000169

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.451A>C (p.T151P) alteration is located in exon 6 (coding exon 6) of the SH3YL1 gene. This alteration results from a A to C substitution at nucleotide position 451, causing the threonine (T) at amino acid position 151 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	.;.;.;D;D;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;.;.;D;D;T
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.3	M;.;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D;.;D;D;D;D;D
Sift4G	Uncertain	0.010	.;D;D;.;.;D;D
Polyphen		0.97	D;D;D;D;D;D;.
Vest4		0.78
MutPred		0.77		Loss of helix (P = 0.079);.;.;Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;.;
MVP		0.52
MPC		0.50
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.73
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1668126350; hg19: chr2-233183;