4-70705219-C-G

Variant names:

• chr4-70705219-C-G
• rs1333124003
• ENST00000417478.6:c.283C>G

Variant summary

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

The NM_001130709.2(RUFY3):​c.283C>G​(p.Pro95Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000763 in 1,309,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict 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. P95S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: RUFY3 NM_001130709.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

Genes affected

RUFY3 (HGNC:30285): (RUN and FYVE domain containing 3) This gene encodes a RPIP8, UNC-14, and NESCA domain-containing protein that is required for maintenance of neuronal polarity. In addition, it has been implicated in mediation of gastric cancer cell migration and invasion via interaction with P21-activated kinase-1, which promotes its expression. The encoded protein localizes to F-actin-enriched invadopodia to induce formation of protrusions, thereby facilitating cell migration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

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=0.28638333).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130709.2. 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
	RUFY3	NM_001130709.2		c.283C>G	p.Pro95Ala	missense	Exon 1 of 12	NP_001124181.1	Q7L099-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUFY3	ENST00000417478.6	TSL:1	c.283C>G	p.Pro95Ala	missense	Exon 1 of 12	ENSP00000399771.2	Q7L099-2
	RUFY3	ENST00000514898.1	TSL:4	c.283C>G	p.Pro95Ala	missense	Exon 2 of 2	ENSP00000426165.1	D6RH24
	RUFY3	ENST00000947599.1		c.-86C>G		5_prime_UTR	Exon 1 of 19	ENSP00000617658.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.63e-7 AC: 1 AN: 1309926 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 644822

African (AFR) AF: 0.00 AC: 0 AN: 26652

American (AMR) AF: 0.00 AC: 0 AN: 25102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23260

East Asian (EAS) AF: 0.00 AC: 0 AN: 27786

South Asian (SAS) AF: 0.00 AC: 0 AN: 71186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3912

European-Non Finnish (NFE) AF: 9.57e-7 AC: 1 AN: 1045138

Other (OTH) AF: 0.00 AC: 0 AN: 54282

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PROVEAN	Pathogenic	-8.0	D
REVEL	Benign	0.081
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.88	P
Vest4		0.14
MutPred		0.26		Loss of glycosylation at P95 (P = 0.0057)
MVP		0.15
ClinPred		0.96	D
GERP RS		2.8
PromoterAI		-0.074	Neutral
Mutation Taster		=88/12	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1333124003; hg19: chr4-71570936;