4-168375484-A-G

Position:

• chr4-168375484-A-G

Variant summary

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

The NM_001012967.3(DDX60L):​c.4526T>C​(p.Leu1509Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDX60L NM_001012967.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

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]

DDX60L (HGNC:):

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	Protein	UniProt
DDX60L	NM_001012967.3	c.4526T>C	p.Leu1509Ser	missense_variant	34/38	ENST00000682922.1	NP_001012985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX60L	ENST00000682922.1	c.4526T>C	p.Leu1509Ser	missense_variant	34/38		NM_001012967.3	ENSP00000507872.1
DDX60L	ENST00000511577.5	c.4526T>C	p.Leu1509Ser	missense_variant	34/38	5		ENSP00000422423.1
DDX60L	ENST00000510590.1	n.1502T>C		non_coding_transcript_exon_variant	5/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 10, 2024

The c.4526T>C (p.L1509S) alteration is located in exon 34 (coding exon 33) of the DDX60L gene. This alteration results from a T to C substitution at nucleotide position 4526, causing the leucine (L) at amino acid position 1509 to be replaced by a serine (S). 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	Pathogenic	0.57
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.058
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.073	N
M_CAP	Benign	0.0067	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Vest4		0.55
MutPred		0.67		Loss of stability (P = 0.0176);Loss of stability (P = 0.0176);
MVP		0.12
MPC		0.20
ClinPred		0.91	D
GERP RS		2.2
gMVP		0.24

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: chr4-169296635;