17-49969709-C-A

Position:

chr17-49969709-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138281.3(DLX4):c.241C>A(p.Pro81Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000306 in 1,601,840 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 0.000026 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

DLX4
NM_138281.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.06

Variant links:

Genes affected

DLX4 (HGNC:2917): (distal-less homeobox 4) Many vertebrate homeo box-containing genes have been identified on the basis of their sequence similarity with Drosophila developmental genes. Members of the Dlx gene family contain a homeobox that is related to that of Distal-less (Dll), a gene expressed in the head and limbs of the developing fruit fly. The Distal-less (Dlx) family of genes comprises at least 6 different members, DLX1-DLX6. The DLX proteins are postulated to play a role in forebrain and craniofacial development. Three transcript variants have been described for this gene, however, the full length nature of one variant has not been described. Studies of the two splice variants revealed that one encoded isoform functions as a repressor of the beta-globin gene while the other isoform lacks that function. [provided by RefSeq, Jul 2008]

DLX4 links:

DLX4 (HGNC:):

DLX4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09787896).

BS2

High AC in GnomAdExome4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLX4	NM_138281.3 linkuse as main transcript	c.241C>A	p.Pro81Thr	missense_variant	1/3	ENST00000240306.5	NP_612138.1	Q92988-1
DLX4	XM_047435517.1 linkuse as main transcript	c.-3297C>A		5_prime_UTR_variant	2/3		XP_047291473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DLX4	ENST00000240306.5 linkuse as main transcript	c.241C>A	p.Pro81Thr	missense_variant	1/3	1	NM_138281.3	ENSP00000240306.3	Q92988-1
DLX4	ENST00000503410.1 linkuse as main transcript	n.165C>A		non_coding_transcript_exon_variant	2/4	4
DLX4	ENST00000505318.2 linkuse as main transcript	n.380C>A		non_coding_transcript_exon_variant	1/2	3
DLX4	ENST00000706528.1 linkuse as main transcript	n.1122C>A		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00000416

AC:

AN:

240332

Hom.:

AF XY:

0.00000765

AC XY:

AN XY:

130740

show subpopulations

Gnomad AFR exome

AF:

0.0000627

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1449746

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

721614

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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

Bravo

AF:

0.0000227

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

Nov 06, 2023

The c.241C>A (p.P81T) alteration is located in exon 1 (coding exon 1) of the DLX4 gene. This alteration results from a C to A substitution at nucleotide position 241, causing the proline (P) at amino acid position 81 to be replaced by a threonine (T). 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

0.069

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.0090

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.43

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.32

REVEL

Benign

0.090

Sift

Benign

0.38

Sift4G

Benign

0.80

Polyphen

0.0010

Vest4

0.16

MutPred

0.19

Loss of stability (P = 0.1343);

MVP

0.93

MPC

0.41

ClinPred

0.058

GERP RS

2.5

Varity_R

0.090

gMVP

0.33

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