17-49969542-C-G

Variant names:

• chr17-49969542-C-G
• rs145781048
• NM_138281.3:c.74C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138281.3(DLX4):​c.74C>G​(p.Pro25Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,613,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: DLX4 NM_138281.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.296
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• orofacial cleft 15

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00781101).
• BP6: Variant 17-49969542-C-G is Benign according to our data. Variant chr17-49969542-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3036294.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 142 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138281.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLX4	NM_138281.3	MANE Select	c.74C>G	p.Pro25Arg	missense	Exon 1 of 3	NP_612138.1	Q92988-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLX4	ENST00000240306.5	TSL:1 MANE Select	c.74C>G	p.Pro25Arg	missense	Exon 1 of 3	ENSP00000240306.3	Q92988-1
	DLX4	ENST00000505318.2	TSL:3	n.213C>G		non_coding_transcript_exon	Exon 1 of 2
	DLX4	ENST00000705772.1		n.74C>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000520982.1	A0ABJ7H8D3

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152186 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000256 AC: 64 AN: 250022 AF XY: 0.000192

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000808 AC: 118 AN: 1460960 Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45 AN XY: 726844

African (AFR) AF: 0.00320 AC: 107 AN: 33468

American (AMR) AF: 0.000112 AC: 5 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111934

Other (OTH) AF: 0.0000828 AC: 5 AN: 60386

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152304 Hom.: 0 Cov.: 31 AF XY: 0.000859 AC XY: 64 AN XY: 74470

African (AFR) AF: 0.00334 AC: 139 AN: 41586

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000918

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000305 AC: 37

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	DLX4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.39	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.30
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.15
Sift	Benign	0.18	T
Sift4G	Uncertain	0.045	D
Polyphen		0.0040	B
Vest4		0.13
MVP		0.87
MPC		0.31
ClinPred		0.011	T
GERP RS		0.64
PromoterAI		0.063	Neutral
Varity_R		0.055
gMVP		0.31
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145781048; hg19: chr17-48046906;