Genetic Variant DMBX1:p.Arg118Trp (chr1-46510953-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_172225.2(DMBX1):c.352C>T(p.Arg118Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,454,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

DMBX1
NM_172225.2 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.82

Publications

2 publications found

Variant links:

Genes affected

DMBX1 (HGNC:19026): (diencephalon/mesencephalon homeobox 1) This gene encodes a member of the bicoid sub-family of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and may play a role in brain and sensory organ development. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

DMBX1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

DMBX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 1-46510953-C-T is Pathogenic according to our data. Variant chr1-46510953-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 183286.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMBX1	NM_172225.2 link	c.352C>T	p.Arg118Trp	missense_variant	Exon 5 of 6	ENST00000360032.4	NP_757379.1	Q8NFW5-2
DMBX1	NM_001387776.1 link	c.367C>T	p.Arg123Trp	missense_variant	Exon 4 of 5		NP_001374705.1
DMBX1	NM_147192.4 link	c.367C>T	p.Arg123Trp	missense_variant	Exon 5 of 6		NP_671725.1	Q8NFW5-1
DMBX1	NM_001387775.1 link	c.352C>T	p.Arg118Trp	missense_variant	Exon 4 of 5		NP_001374704.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMBX1	ENST00000360032.4 link	c.352C>T	p.Arg118Trp	missense_variant	Exon 5 of 6	1	NM_172225.2	ENSP00000353132.3		Q8NFW5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000413

AC:

AN:

1454406

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722770

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33280

American (AMR)

AF:

0.00

AC:

AN:

43972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25598

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1107786

Other (OTH)

AF:

0.0000333

AC:

AN:

60036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hypermetropia;C0026827:Hypotonia;C0036572:Seizure;C0038379:Strabismus;C0557874:Global developmental delay;C1384666:Hearing impairment

Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

5.0

H;.

PhyloP100

1.8

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.91

Loss of disorder (P = 0.0104);.;

MVP

0.99

MPC

1.1

ClinPred

1.0

GERP RS

2.5

Varity_R

0.87

gMVP

0.99

Mutation Taster

=1/99

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over