4-168221841-G-A

Position:

• chr4-168221841-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017631.6(DDX60):​c.4865C>T​(p.Pro1622Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDX60 NM_017631.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.28

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX60	NM_017631.6	c.4865C>T	p.Pro1622Leu	missense_variant	36/38	ENST00000393743.8	NP_060101.3
DDX60	NM_001410861.1	c.4865C>T	p.Pro1622Leu	missense_variant	36/38		NP_001397790.1
DDX60	XM_024454132.2	c.4865C>T	p.Pro1622Leu	missense_variant	37/39		XP_024309900.1
DDX60	XM_024454133.2	c.4865C>T	p.Pro1622Leu	missense_variant	36/38		XP_024309901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX60	ENST00000393743.8	c.4865C>T	p.Pro1622Leu	missense_variant	36/38	1	NM_017631.6	ENSP00000377344.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jul 06, 2024

The c.4865C>T (p.P1622L) alteration is located in exon 36 (coding exon 35) of the DDX60 gene. This alteration results from a C to T substitution at nucleotide position 4865, causing the proline (P) at amino acid position 1622 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	0.23
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.34
Sift	Benign	0.031	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.52		Loss of loop (P = 0.0203);
MVP		0.50
MPC		0.65
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.34
gMVP		0.64

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: chr4-169142992;