2-218072878-C-G

Variant names:

• chr2-218072878-C-G
• rs781607906
• NM_198483.4:c.379C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198483.4(RUFY4):​c.379C>G​(p.Leu127Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,378,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 7.3e-7 (0 hom.)
• Consequence: RUFY4 NM_198483.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0410
• Publications: 1 publications found

Genes affected

RUFY4 (HGNC:24804): (RUN and FYVE domain containing 4) Enables phosphatidylinositol-3-phosphate binding activity. Involved in autophagosome assembly; cellular response to interleukin-4; and positive regulation of macroautophagy. Located in autophagosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06720984).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198483.4. 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
	RUFY4	NM_198483.4	MANE Select	c.379C>G	p.Leu127Val	missense	Exon 6 of 13	NP_940885.2	Q6ZNE9-2
	RUFY4	NR_034176.2		n.1766-365C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUFY4	ENST00000697321.1	MANE Select	c.379C>G	p.Leu127Val	missense	Exon 6 of 13	ENSP00000513250.1	Q6ZNE9-2
	RUFY4	ENST00000374155.7	TSL:2	c.379C>G	p.Leu127Val	missense	Exon 5 of 12	ENSP00000363270.3	C9J235
	RUFY4	ENST00000344321.8	TSL:5	c.379C>G	p.Leu127Val	missense	Exon 4 of 11	ENSP00000345900.7	Q6ZNE9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000745 AC: 1 AN: 134304 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1378130 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 679768

African (AFR) AF: 0.00 AC: 0 AN: 31238

American (AMR) AF: 0.00 AC: 0 AN: 34286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24690

East Asian (EAS) AF: 0.00 AC: 0 AN: 35720

South Asian (SAS) AF: 0.00 AC: 0 AN: 78278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075790

Other (OTH) AF: 0.00 AC: 0 AN: 57608

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000413 AC: 1

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	0.092
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.041
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.036
Sift	Benign	0.15	T
Sift4G	Uncertain	0.021	D
Vest4		0.19
MutPred		0.62		Loss of stability (P = 0.105)
MVP		0.20
MPC		0.060
ClinPred		0.082	T
GERP RS		3.2
Varity_R		0.041
gMVP		0.19
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

dbSNP: rs781607906; hg19: chr2-218937601;