4-168371745-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001012967.3(DDX60L):c.4795G>A(p.Gly1599Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,603,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DDX60L NM_001012967.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07843602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX60L	NM_001012967.3	c.4795G>A	p.Gly1599Ser	missense_variant	36/38	ENST00000682922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX60L	ENST00000682922.1	c.4795G>A	p.Gly1599Ser	missense_variant	36/38		NM_001012967.3
DDX60L	ENST00000511577.5	c.4795G>A	p.Gly1599Ser	missense_variant	36/38	5		P1
DDX60L	ENST00000510590.1	n.1771G>A		non_coding_transcript_exon_variant	7/9	2

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152018 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000109 AC: 27 AN: 247764 Hom.: 0 AF XY: 0.000112 AC XY: 15 AN XY: 134410

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000511

Gnomad NFE exome AF: 0.0000801

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.000133 AC: 193 AN: 1451856 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 88 AN XY: 722558

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.000396

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.000167

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152018 Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6 AN XY: 74228

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.0000992 AC: 12

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

Apr 28, 2023

The c.4795G>A (p.G1599S) alteration is located in exon 36 (coding exon 35) of the DDX60L gene. This alteration results from a G to A substitution at nucleotide position 4795, causing the glycine (G) at amino acid position 1599 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	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	18
Dann	Benign	0.61
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.043	N
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.046
Sift	Benign	0.14	T;T
Sift4G	Benign	0.21	T;T
Vest4		0.37
MVP		0.030
MPC		0.029
ClinPred		0.042	T
GERP RS		1.9
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199671577; hg19: chr4-169292896;