NM_004728.4:c.524T>A

Variant names:

• chr10-68960242-T-A
• rs368402384
• NM_004728.4:c.524T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004728.4(DDX21):​c.524T>A​(p.Ile175Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I175T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DDX21 NM_004728.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.200
• Publications: 1 publications found

Genes affected

DDX21 (HGNC:2744): (DExD-box helicase 21) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which is an antigen recognized by autoimmune antibodies from a patient with watermelon stomach disease. This protein unwinds double-stranded RNA, folds single-stranded RNA, and may play important roles in ribosomal RNA biogenesis, RNA editing, RNA transport, and general transcription. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033356875).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004728.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX21	NM_004728.4	MANE Select	c.524T>A	p.Ile175Lys	missense	Exon 2 of 15	NP_004719.2	Q9NR30-1
	DDX21	NM_001410932.1		c.524T>A	p.Ile175Lys	missense	Exon 2 of 14	NP_001397861.1	A0A8I5KYZ4
	DDX21	NM_001256910.2		c.320T>A	p.Ile107Lys	missense	Exon 2 of 15	NP_001243839.1	Q9NR30-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX21	ENST00000354185.9	TSL:1 MANE Select	c.524T>A	p.Ile175Lys	missense	Exon 2 of 15	ENSP00000346120.4	Q9NR30-1
	DDX21	ENST00000620315.2	TSL:1	c.320T>A	p.Ile107Lys	missense	Exon 2 of 15	ENSP00000480334.1	Q9NR30-2
	DDX21	ENST00000684824.1		c.524T>A	p.Ile175Lys	missense	Exon 2 of 16	ENSP00000508611.1	A0A8I5KNN2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.3
DANN	Benign	0.37
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.20
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.055
Sift	Benign	0.91	T
Sift4G	Benign	0.82	T
Polyphen		0.0050	B
Vest4		0.22
MutPred		0.36		Gain of ubiquitination at I175 (P = 0.0037)
MVP		0.23
MPC		0.14
ClinPred		0.055	T
GERP RS		-2.9
Varity_R		0.091
gMVP		0.23
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs368402384; hg19: chr10-70719998;