4-168236370-G-A

Position:

• chr4-168236370-G-A

Variant summary

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

The NM_017631.6(DDX60):​c.4415C>T​(p.Ser1472Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000414 in 1,448,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000041 (0 hom.)
• Consequence: DDX60 NM_017631.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

Genes affected

DDX60 (HGNC:25942): (DExD/H-box helicase 60) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases which are implicated in a number of cellular procsses involving RNA binding and alteration of RNA secondary structure. This gene encodes a DEXD/H box RNA helicase that functions as an antiviral factor and promotes RIG-I-like receptor-mediated signaling. [provided by RefSeq, Apr 2017]

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=0.22291613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX60	NM_017631.6	c.4415C>T	p.Ser1472Leu	missense_variant	33/38	ENST00000393743.8	NP_060101.3
DDX60	NM_001410861.1	c.4415C>T	p.Ser1472Leu	missense_variant	33/38		NP_001397790.1
DDX60	XM_024454132.2	c.4415C>T	p.Ser1472Leu	missense_variant	34/39		XP_024309900.1
DDX60	XM_024454133.2	c.4415C>T	p.Ser1472Leu	missense_variant	33/38		XP_024309901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX60	ENST00000393743.8	c.4415C>T	p.Ser1472Leu	missense_variant	33/38	1	NM_017631.6	ENSP00000377344	P2
DDX60	ENST00000680771.1	c.4415C>T	p.Ser1472Leu	missense_variant	33/38			ENSP00000505292	A2
DDX60	ENST00000507815.1	n.207C>T		non_coding_transcript_exon_variant	2/2	2
DDX60	ENST00000679510.1	c.*354C>T		3_prime_UTR_variant, NMD_transcript_variant	34/39			ENSP00000506501

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1448854 Hom.: 0 Cov.: 29 AF XY: 0.00000555 AC XY: 4 AN XY: 720760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 18, 2022

The c.4415C>T (p.S1472L) alteration is located in exon 33 (coding exon 32) of the DDX60 gene. This alteration results from a C to T substitution at nucleotide position 4415, causing the serine (S) at amino acid position 1472 to be replaced by a leucine (L). 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	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	0.67	N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.14
Sift	Benign	0.054	T
Sift4G	Uncertain	0.018	D
Polyphen		0.85	P
Vest4		0.26
MutPred		0.39		Gain of catalytic residue at S1472 (P = 0.0048);
MVP		0.17
MPC		0.26
ClinPred		0.94	D
GERP RS		4.4
Varity_R		0.33
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs1221587237; hg19: chr4-169157521; COSMIC: COSV101190172; COSMIC: COSV101190172;