NM_001037442.4:c.218T>C

Variant names:

• chr4-70762558-T-C
• NM_001037442.4:c.218T>C

Variant summary

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

The NM_001037442.4(RUFY3):​c.218T>C​(p.Met73Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RUFY3 NM_001037442.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• 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 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037442.4. 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
	RUFY3	NM_001037442.4	MANE Select	c.218T>C	p.Met73Thr	missense	Exon 2 of 18	NP_001032519.1	Q7L099-3
	RUFY3	NM_001291993.2		c.59T>C	p.Met20Thr	missense	Exon 3 of 19	NP_001278922.1	Q7L099-4
	RUFY3	NM_001130709.2		c.398T>C	p.Met133Thr	missense	Exon 2 of 12	NP_001124181.1	Q7L099-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUFY3	ENST00000381006.8	TSL:5 MANE Select	c.218T>C	p.Met73Thr	missense	Exon 2 of 18	ENSP00000370394.3	Q7L099-3
	RUFY3	ENST00000417478.6	TSL:1	c.398T>C	p.Met133Thr	missense	Exon 2 of 12	ENSP00000399771.2	Q7L099-2
	RUFY3	ENST00000226328.8	TSL:1	c.218T>C	p.Met73Thr	missense	Exon 2 of 13	ENSP00000226328.4	Q7L099-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461320 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726850

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

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111602

Other (OTH) AF: 0.00 AC: 0 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.0	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.81	P
Vest4		0.78
MutPred		0.29		Loss of MoRF binding (P = 0.1046)
MVP		0.31
MPC		2.2
ClinPred		0.97	D
GERP RS		6.2
Varity_R		0.57
gMVP		0.95
Mutation Taster		=24/76	disease causing

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

Other links and lift over

hg19: chr4-71628275;