2-15604448-G-T

Variant names:

• chr2-15604448-G-T
• rs201032703
• NM_004939.3:c.564G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004939.3(DDX1):​c.564G>T​(p.Met188Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DDX1 NM_004939.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.03
• Publications: 0 publications found

Genes affected

DDX1 (HGNC:2734): (DEAD-box helicase 1) 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 that acts as an ATP-dependent RNA helicase that has been found to promote coronaviruses replication. [provided by RefSeq, Aug 2021]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32992044).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004939.3. 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
	DDX1	NM_004939.3	MANE Select	c.564G>T	p.Met188Ile	missense	Exon 10 of 26	NP_004930.1	Q92499-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX1	ENST00000233084.8	TSL:1 MANE Select	c.564G>T	p.Met188Ile	missense	Exon 10 of 26	ENSP00000233084.3	Q92499-1
	DDX1	ENST00000617198.5	TSL:1	c.288G>T	p.Met96Ile	missense	Exon 8 of 24	ENSP00000482416.2	A0A087WZ71
	DDX1	ENST00000381341.7	TSL:5	c.564G>T	p.Met188Ile	missense	Exon 11 of 27	ENSP00000370745.1	Q92499-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457100 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725316

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108062

Other (OTH) AF: 0.00 AC: 0 AN: 60244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Benign	0.89
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L
PhyloP100		9.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.27
Sift	Benign	0.31	T
Sift4G	Benign	0.32	T
Polyphen		0.51	P
Vest4		0.64
MutPred		0.44		Loss of disorder (P = 0.1004)
MVP		0.67
MPC		0.30
ClinPred		0.67	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.42
Mutation Taster		=54/46	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: rs201032703; hg19: chr2-15744572;