1-46512214-G-C

Position:

• chr1-46512214-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_172225.2(DMBX1):​c.854G>C​(p.Gly285Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,614,044 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G285C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (7 hom.)
• Consequence: DMBX1 NM_172225.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.16

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008773148).
• BP6: Variant 1-46512214-G-C is Benign according to our data. Variant chr1-46512214-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3049412.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMBX1	NM_172225.2	c.854G>C	p.Gly285Ala	missense_variant	6/6	ENST00000360032.4
DMBX1	NM_001387776.1	c.869G>C	p.Gly290Ala	missense_variant	5/5
DMBX1	NM_147192.4	c.869G>C	p.Gly290Ala	missense_variant	6/6
DMBX1	NM_001387775.1	c.854G>C	p.Gly285Ala	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMBX1	ENST00000360032.4	c.854G>C	p.Gly285Ala	missense_variant	6/6	1	NM_172225.2	P1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00159 AC: 398 AN: 250798 Hom.: 3 AF XY: 0.00147 AC XY: 200 AN XY: 135716

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.00222 AC: 3250 AN: 1461796 Hom.: 7 Cov.: 31 AF XY: 0.00219 AC XY: 1589 AN XY: 727220

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.00277

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74440

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00280 Hom.: 0

Bravo AF: 0.00162

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00179 AC: 217

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00344

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DMBX1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 16, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.066	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.16	N;N
REVEL	Benign	0.16
Sift	Benign	0.24	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.0030	B;B
Vest4		0.070
MVP		0.64
MPC		0.37
ClinPred		0.0078	T
GERP RS		2.3
Varity_R		0.054
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs114486361; hg19: chr1-46977886;