2-218888-A-C

Variant names:

• chr2-218888-A-C
• rs374187755
• NM_015677.4:c.952T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015677.4(SH3YL1):​c.952T>G​(p.Ser318Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S318P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SH3YL1 NM_015677.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38975522).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015677.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3YL1	NM_015677.4	MANE Select	c.952T>G	p.Ser318Ala	missense	Exon 10 of 10	NP_056492.2	Q96HL8-1
	SH3YL1	NM_001159597.3		c.895T>G	p.Ser299Ala	missense	Exon 9 of 9	NP_001153069.1	Q96HL8-2
	SH3YL1	NM_001282687.2		c.664T>G	p.Ser222Ala	missense	Exon 12 of 12	NP_001269616.1	Q96HL8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3YL1	ENST00000356150.10	TSL:1 MANE Select	c.952T>G	p.Ser318Ala	missense	Exon 10 of 10	ENSP00000348471.5	Q96HL8-1
	SH3YL1	ENST00000403712.6	TSL:1	c.895T>G	p.Ser299Ala	missense	Exon 9 of 9	ENSP00000384276.1	Q96HL8-2
	SH3YL1	ENST00000626873.2	TSL:5	c.664T>G	p.Ser222Ala	missense	Exon 13 of 13	ENSP00000485824.1	Q96HL8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.26
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.021	D
Polyphen		0.87	P
Vest4		0.33
MutPred		0.45		Gain of catalytic residue at S318 (P = 0.0651)
MVP		0.69
MPC		0.29
ClinPred		0.86	D
GERP RS		6.0
Varity_R		0.15
gMVP		0.47
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs374187755; hg19: chr2-218888;