4-168394607-C-T

Variant names:

• chr4-168394607-C-T
• rs778220209
• NM_001012967.3:c.3668G>A

Variant summary

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

The NM_001012967.3(DDX60L):​c.3668G>A​(p.Arg1223Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 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. R1223M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DDX60L NM_001012967.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.956
• Publications: 1 publications found

Genes affected

DDX60L (HGNC:26429): (DExD/H-box 60 like) This gene encodes a member of the DExD/H-box helicase family of proteins, a subset of the super family 2 helicases. Members of the DExD/H-box helicase family share a conserved functional core comprised of two RecA-like globular domains. These domains contain conserved motifs that mediate ATP binding, ATP hydrolysis, nucleic acid binding, and RNA unwinding. In addition to functions in RNA metabolism, members of this family are involved in anti-viral immunity and act as cytosolic sensors of viral nucleic acids. The protein encoded by this gene has been shown to inhibit hepatitis C virus replication in response to interferon stimulation in cell culture. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

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=0.0064541698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX60L	NM_001012967.3	c.3668G>A	p.Arg1223Lys	missense_variant	Exon 28 of 38	ENST00000682922.1	NP_001012985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX60L	ENST00000682922.1	c.3668G>A	p.Arg1223Lys	missense_variant	Exon 28 of 38		NM_001012967.3	ENSP00000507872.1
DDX60L	ENST00000511577.5	c.3668G>A	p.Arg1223Lys	missense_variant	Exon 28 of 38	5		ENSP00000422423.1
DDX60L	ENST00000505890.5	c.3671G>A	p.Arg1224Lys	missense_variant	Exon 28 of 30	2		ENSP00000422202.1
DDX60L	ENST00000514580.5	c.329G>A	p.Arg110Lys	missense_variant	Exon 3 of 5	5		ENSP00000422920.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.0030
DANN	Benign	0.45
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0019	N
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.0065	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.96
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.3	N;N;N
REVEL	Benign	0.096
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Vest4		0.021
MutPred		0.43		Loss of catalytic residue at R1223 (P = 0.0394);Loss of catalytic residue at R1223 (P = 0.0394);.;
MVP		0.048
MPC		0.023
ClinPred		0.054	T
GERP RS		-6.6
gMVP		0.10
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778220209; hg19: chr4-169315758; COSMIC: COSV52710491; COSMIC: COSV52710491;