4-70705219-C-T

Variant names:

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

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>T​(p.Pro95Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,678 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: RUFY3 NM_001130709.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.26798213).

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>T	p.Pro95Ser	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>T	p.Pro95Ser	missense	Exon 1 of 12	ENSP00000399771.2	Q7L099-2
	RUFY3	ENST00000514898.1	TSL:4	c.283C>T	p.Pro95Ser	missense	Exon 2 of 2	ENSP00000426165.1	D6RH24
	RUFY3	ENST00000947599.1		c.-86C>T		5_prime_UTR	Exon 1 of 19	ENSP00000617658.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151752 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000840 AC: 11 AN: 1309926 Hom.: 0 Cov.: 31 AF XY: 0.0000109 AC XY: 7 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: 0.0000720 AC: 2 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: 0.00000765 AC: 8 AN: 1045138

Other (OTH) AF: 0.0000184 AC: 1 AN: 54282

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151752 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67914

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PROVEAN	Pathogenic	-8.0	D
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.94	P
Vest4		0.18
MutPred		0.26		Loss of glycosylation at P95 (P = 0.0057)
MVP		0.13
ClinPred		0.99	D
GERP RS		2.8
PromoterAI		0.0078	Neutral
Mutation Taster		=90/10	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; COSMIC: COSV65914150; COSMIC: COSV65914150;