4-168221856-T-C

Position:

• chr4-168221856-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000393743.8(DDX60):​c.4850A>G​(p.Asn1617Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,612,998 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (30 hom.)
• Consequence: DDX60 ENST00000393743.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.983

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023328066).
• BP6: Variant 4-168221856-T-C is Benign according to our data. Variant chr4-168221856-T-C is described in ClinVar as [Benign]. Clinvar id is 784490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1694/152274) while in subpopulation AFR AF= 0.0352 (1465/41566). AF 95% confidence interval is 0.0337. There are 17 homozygotes in gnomad4. There are 804 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX60	NM_017631.6	c.4850A>G	p.Asn1617Ser	missense_variant	36/38	ENST00000393743.8	NP_060101.3
DDX60	NM_001410861.1	c.4850A>G	p.Asn1617Ser	missense_variant	36/38		NP_001397790.1
DDX60	XM_024454132.2	c.4850A>G	p.Asn1617Ser	missense_variant	37/39		XP_024309900.1
DDX60	XM_024454133.2	c.4850A>G	p.Asn1617Ser	missense_variant	36/38		XP_024309901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX60	ENST00000393743.8	c.4850A>G	p.Asn1617Ser	missense_variant	36/38	1	NM_017631.6	ENSP00000377344	P2
DDX60	ENST00000680771.1	c.4850A>G	p.Asn1617Ser	missense_variant	36/38			ENSP00000505292	A2
DDX60	ENST00000511317.2	c.329A>G	p.Asn110Ser	missense_variant	4/5	3		ENSP00000422669
DDX60	ENST00000679510.1	c.*789A>G		3_prime_UTR_variant, NMD_transcript_variant	37/39			ENSP00000506501

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1689 AN: 152156 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00976

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00345 AC: 865 AN: 250560 Hom.: 12 AF XY: 0.00280 AC XY: 379 AN XY: 135410

Gnomad AFR exome AF: 0.0360

Gnomad AMR exome AF: 0.00397

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000645

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.00158 AC: 2304 AN: 1460724 Hom.: 30 Cov.: 30 AF XY: 0.00150 AC XY: 1088 AN XY: 726594

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.00459

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000481

Gnomad4 OTH exome AF: 0.00399

GnomAD4 genome AF: 0.0111 AC: 1694 AN: 152274 Hom.: 17 Cov.: 32 AF XY: 0.0108 AC XY: 804 AN XY: 74434

Gnomad4 AFR AF: 0.0352

Gnomad4 AMR AF: 0.00975

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00245 Hom.: 7

Bravo AF: 0.0130

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0336 AC: 148

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00369 AC: 448

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.000658

EpiControl AF: 0.000535

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.018
DANN	Benign	0.38
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.78	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.016
Sift	Benign	0.92	T
Sift4G	Benign	0.41	T
Polyphen		0.013	B
Vest4		0.065
MVP		0.11
MPC		0.12
ClinPred		0.0083	T
GERP RS		-6.0
Varity_R		0.070
gMVP		0.10

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

Other links and lift over

dbSNP: rs150280711; hg19: chr4-169143007;