5-119118957-T-C

Position:

chr5-119118957-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001290321.3(DMXL1):c.886T>C(p.Phe296Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

DMXL1
NM_001290321.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.497

Variant links:

Genes affected

DMXL1 (HGNC:2937): (Dmx like 1) The protein encoded by this gene is a member of the WD repeat superfamily of proteins, which have regulatory functions. This gene is expressed in many tissue types including several types of eye tissue, and it has been associated with ocular phenotypes. In addition, it is upregulated in cultured cells that overexpress growth factor independence 1B, a transcription factor that is essential for hematopoietic cell development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

DMXL1 links:

DMXL1 (HGNC:):

DMXL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05279857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMXL1	NM_001290321.3 linkuse as main transcript	c.886T>C	p.Phe296Leu	missense_variant	8/44	ENST00000539542.6	NP_001277250.1	Q9Y485B2RWN7F5H269F1T0K4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DMXL1	ENST00000539542.6 linkuse as main transcript	c.886T>C	p.Phe296Leu	missense_variant	8/44	1	NM_001290321.3	ENSP00000439479.1	F5H269
DMXL1	ENST00000311085.8 linkuse as main transcript	c.886T>C	p.Phe296Leu	missense_variant	8/43	1		ENSP00000309690.8	Q9Y485
DMXL1	ENST00000503802.5 linkuse as main transcript	c.886T>C	p.Phe296Leu	missense_variant	9/13	1		ENSP00000427692.1	E7EMZ0
DMXL1	ENST00000514151.1 linkuse as main transcript	n.416-2014T>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250546

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461206

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726846

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.886T>C (p.F296L) alteration is located in exon 8 (coding exon 8) of the DMXL1 gene. This alteration results from a T to C substitution at nucleotide position 886, causing the phenylalanine (F) at amino acid position 296 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.013

T;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.053

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.84

.;.;L

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.81

N;N;N

REVEL

Benign

0.040

Sift

Benign

0.77

T;T;T

Sift4G

Benign

1.0

T;.;.

Polyphen

0.0

.;B;B

Vest4

0.28, 0.32

MutPred

0.21

Loss of methylation at K297 (P = 0.0289);Loss of methylation at K297 (P = 0.0289);Loss of methylation at K297 (P = 0.0289);

MVP

0.13

MPC

0.063

ClinPred

0.020

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.043

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over