dbSNP rs141601766: DDX41:p.Met1? (chr5-177516943-C-T) – ACMG Classification: Pathogenic (22 pts)

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS1_ModeratePS3PP5_Very_Strong

The NM_016222.4(DDX41):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000174 in 1,612,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001438362: Functional studies of p.Met1Ile indicate that an alternate, downstream methioinine is used for initiation of translation and that the resulting protein is mislocalized because it lacks a nuclear locationization signal." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

DDX41
NM_016222.4 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16U:1O:2

Conservation

PhyloP100: 3.79

Publications

31 publications found

Variant links:

Genes affected

DDX41 (HGNC:18674): (DEAD-box helicase 41) 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 the DEAD box protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The protein encoded by this gene is a member of the DEAD box protein family and interacts with several spliceosomal proteins. In addition, the encoded protein may recognize the bacterial second messengers cyclic di-GMP and cyclic di-AMP, resulting in the induction of genes involved in the innate immune response. [provided by RefSeq, Jan 2017]

DDX41 Gene-Disease associations (from GenCC):

DDX41-related hematologic malignancy predisposition syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, ClinGen
acromesomelic dysplasia
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

DDX41 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 22 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 27 pathogenic variants. Next in-frame start position is after 127 codons. Genomic position: 177515984. Lost 0.203 part of the original CDS.

PS1

Another start lost variant in NM_016222.4 (DDX41) was described as [Pathogenic] in ClinVar

PS3

PS3 evidence extracted from ClinVar submissions: SCV001438362: Functional studies of p.Met1Ile indicate that an alternate, downstream methioinine is used for initiation of translation and that the resulting protein is mislocalized because it lacks a nuclear locationization signal.; SCV002034839: Expression studies in HEK cells illustrate the p.Met1Ile variant exhibits altered cellular localization when compared to wildtype DDX41 (Lewinsohn et al. 2016).; SCV002049719: Functional analyses of the variant protein demonstrate reduced protein size, supporting altered translation and subcellular localization (Lewinsohn 2016). PMID: 26712909; SCV002070517: Studies have shown that the disruption of the initiating methionine resulted in a predominant smaller protein (PMID: 26712909).; SCV000617985: Published functional studies suggest a damaging effect: shortened protein product that demonstrated altered cellular localization (Lewinsohn et al., 2016); SCV003299840: Experimental studies have shown that disruption of the initiator codon affects DDX41 function (PMID: 26712909).; SCV004723001: Biochemical studies indicate the c.3G>A substitution results in altered translation of a smaller DDX41 protein with improper cellular localization (Lewinsohn et al. 2016. PubMed ID: 26712909).

PP5

Variant 5-177516943-C-T is Pathogenic according to our data. Variant chr5-177516943-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016222.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DDX41	NM_016222.4	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 17	NP_057306.2
DDX41	NM_001321732.2		c.-653G>A		5_prime_UTR	Exon 1 of 16	NP_001308661.1	B3KRK2
DDX41	NM_001321830.2		c.-445G>A		5_prime_UTR	Exon 1 of 17	NP_001308759.1	B3KRK2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DDX41	ENST00000330503.12	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 17	ENSP00000330349.8	Q9UJV9
DDX41	ENST00000507955.6	TSL:1	n.3G>A		non_coding_transcript_exon	Exon 1 of 17	ENSP00000422753.2	A0A499FJW5
DDX41	ENST00000904584.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 17	ENSP00000574643.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000815

AC:

AN:

245476

AF XY:

0.0000825

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000156

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000179

AC:

261

AN:

1460294

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

726318

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33468

American (AMR)

AF:

0.0000224

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.0000573

AC:

AN:

52374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000226

AC:

251

AN:

1111584

Other (OTH)

AF:

0.0000497

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000125

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68042

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000205

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000495

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

DDX41-related hematologic malignancy predisposition syndrome (11)

not provided (4)

Bone marrow hypocellularity (1)

DDX41-related disorder (1)

Inborn genetic diseases (1)

Myelodysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

Eigen

Benign

0.060

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-1.1

PhyloP100

3.8

PROVEAN

Benign

-0.65

REVEL

Benign

0.17

Sift

Uncertain

0.027

Sift4G

Benign

0.25

Polyphen

0.27

Vest4

0.84

MutPred

0.99

Gain of glycosylation at S4 (P = 0.0626)

MVP

0.60

ClinPred

0.70

GERP RS

4.4

PromoterAI

-0.095

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.64

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over