4-70783140-G-A

Position:

• chr4-70783140-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001037442.4(RUFY3):​c.944G>A​(p.Arg315Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,472 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R315G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RUFY3 NM_001037442.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUFY3	NM_001037442.4	c.944G>A	p.Arg315Gln	missense_variant	9/18	ENST00000381006.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUFY3	ENST00000381006.8	c.944G>A	p.Arg315Gln	missense_variant	9/18	5	NM_001037442.4	P1
RUFY3	ENST00000417478.6	c.1124G>A	p.Arg375Gln	missense_variant	9/12	1
RUFY3	ENST00000226328.8	c.944G>A	p.Arg315Gln	missense_variant	9/13	1
RUFY3	ENST00000502653.5	c.785G>A	p.Arg262Gln	missense_variant	10/19	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459472 Hom.: 0 Cov.: 28 AF XY: 0.00000275 AC XY: 2 AN XY: 726168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.944G>A (p.R315Q) alteration is located in exon 9 (coding exon 9) of the RUFY3 gene. This alteration results from a G to A substitution at nucleotide position 944, causing the arginine (R) at amino acid position 315 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	.;.;T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.020	.;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	1.4	N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.95	T;T;T;T
Polyphen		0.19	B;D;D;.
Vest4		0.75
MutPred		0.18		.;Gain of glycosylation at S320 (P = 0.0091);Gain of glycosylation at S320 (P = 0.0091);.;
MVP		0.63
MPC		2.2
ClinPred		0.80	D
GERP RS		5.7
Varity_R		0.23
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-71648857;