rs371028948

Variant names:

• chr10-68383905-C-T
• rs371028948
• NM_001330103.2:c.832G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330103.2(RUFY2):​c.832G>A​(p.Val278Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RUFY2 NM_001330103.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

Genes affected

RUFY2 (HGNC:19761): (RUN and FYVE domain containing 2) Enables SH3 domain binding activity. Predicted to be involved in regulation of endocytosis. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1294859).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUFY2	NM_001330103.2	c.832G>A	p.Val278Ile	missense_variant	Exon 10 of 18	ENST00000602465.6	NP_001317032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUFY2	ENST00000602465.6	c.832G>A	p.Val278Ile	missense_variant	Exon 10 of 18	5	NM_001330103.2	ENSP00000473462.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249032 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460870 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726822

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53074

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111456

Other (OTH) AF: 0.0000166 AC: 1 AN: 60356

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.937G>A (p.V313I) alteration is located in exon 10 (coding exon 10) of the RUFY2 gene. This alteration results from a G to A substitution at nucleotide position 937, causing the valine (V) at amino acid position 313 to be replaced by an isoleucine (I). 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	0.077
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.073
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		5.7
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.55	N;.;N;N
REVEL	Benign	0.045
Sift	Benign	0.19	T;.;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.21
MutPred		0.19		Loss of disorder (P = 0.1867);.;.;.;
MVP		0.33
MPC		0.35
ClinPred		0.20	T
GERP RS		4.2
Varity_R		0.022
gMVP		0.11
Mutation Taster		=85/15	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

Publications

LitVar

Other links and lift over

dbSNP: rs371028948; hg19: chr10-70143662;