2-233213-C-T

Variant names:

• chr2-233213-C-T
• rs373205095
• NM_015677.4:c.421G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_015677.4(SH3YL1):​c.421G>A​(p.Val141Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000451 in 1,573,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V141L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: SH3YL1 NM_015677.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14530715).

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.421G>A	p.Val141Met	missense	Exon 6 of 10	NP_056492.2	Q96HL8-1
	SH3YL1	NM_001159597.3		c.421G>A	p.Val141Met	missense	Exon 6 of 9	NP_001153069.1	Q96HL8-2
	SH3YL1	NM_001282687.2		c.133G>A	p.Val45Met	missense	Exon 8 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.421G>A	p.Val141Met	missense	Exon 6 of 10	ENSP00000348471.5	Q96HL8-1
	SH3YL1	ENST00000403712.6	TSL:1	c.421G>A	p.Val141Met	missense	Exon 6 of 9	ENSP00000384276.1	Q96HL8-2
	SH3YL1	ENST00000626873.2	TSL:5	c.133G>A	p.Val45Met	missense	Exon 9 of 13	ENSP00000485824.1	Q96HL8-3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000615 AC: 14 AN: 227788 AF XY: 0.0000642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000773

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000374

Gnomad OTH exome AF: 0.000371

GnomAD4 exome AF: 0.0000443 AC: 63 AN: 1421516 Hom.: 0 Cov.: 30 AF XY: 0.0000495 AC XY: 35 AN XY: 706564

African (AFR) AF: 0.0000310 AC: 1 AN: 32226

American (AMR) AF: 0.00 AC: 0 AN: 38888

Ashkenazi Jewish (ASJ) AF: 0.000963 AC: 24 AN: 24922

East Asian (EAS) AF: 0.00 AC: 0 AN: 38774

South Asian (SAS) AF: 0.0000749 AC: 6 AN: 80072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.0000229 AC: 25 AN: 1090714

Other (OTH) AF: 0.000120 AC: 7 AN: 58236

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.13
Eigen_PC	Benign	-0.0044
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.91	P
Vest4		0.62
MVP		0.25
MPC		0.39
ClinPred		0.25	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.74
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs373205095; hg19: chr2-233213;