4-168361164-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001012967.3(DDX60L):c.4976A>G(p.Asn1659Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,608,064 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 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

DDX60L
NM_001012967.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.285

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019659728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX60L	NM_001012967.3 linkuse as main transcript	c.4976A>G	p.Asn1659Ser	missense_variant	37/38	ENST00000682922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DDX60L	ENST00000682922.1 linkuse as main transcript	c.4976A>G	p.Asn1659Ser	missense_variant	37/38		NM_001012967.3
DDX60L	ENST00000511577.5 linkuse as main transcript	c.4976A>G	p.Asn1659Ser	missense_variant	37/38	5		P1
DDX60L	ENST00000510590.1 linkuse as main transcript	n.1952A>G		non_coding_transcript_exon_variant	8/9	2
DDX60L	ENST00000513103.1 linkuse as main transcript	n.276A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000106

AC:

AN:

244260

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

132372

show subpopulations

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 SAS exome

AF:

0.000539

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000906

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000113

AC:

165

AN:

1455828

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

724102

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000269

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000114

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000244

AC:

ExAC

AF:

0.000108

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2023

The c.4976A>G (p.N1659S) alteration is located in exon 37 (coding exon 36) of the DDX60L gene. This alteration results from a A to G substitution at nucleotide position 4976, causing the asparagine (N) at amino acid position 1659 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

0.071

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.82

Cadd

Benign

8.0

Dann

Benign

0.85

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0043

M_CAP

Benign

0.0012

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.31

N;N

REVEL

Benign

0.016

Sift

Benign

0.40

T;T

Sift4G

Benign

0.16

T;T

Vest4

0.084

MVP

0.030

MPC

0.021

ClinPred

0.017

GERP RS

-4.1

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over