7-97006051-G-GGCA

Position:

• chr7-97006051-G-GGCA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3 BS2

The NM_005222.4(DLX6):​c.96_98dupGCA​(p.Gln33dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,582,026 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 29)
  • Exomes 𝑓: 0.00089 (1 hom.)
• Consequence: DLX6 NM_005222.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 2.11

Genes affected

DLX6 (HGNC:2919): (distal-less homeobox 6) This gene encodes a member of a homeobox transcription factor gene family similiar to the Drosophila distal-less gene. This family is comprised of at least 6 different members that encode proteins with roles in forebrain and craniofacial development. This gene is in a tail-to-tail configuration with another member of the family on the long arm of chromosome 7. [provided by RefSeq, Jul 2008]

DLX6-AS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005222.4
• BS2: High AC in GnomAd4 at 308 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLX6	NM_005222.4	c.96_98dupGCA	p.Gln33dup	disruptive_inframe_insertion	1/3	ENST00000518156.3	NP_005213.3
DLX6-AS1	NR_015448.1	n.141+7871_141+7873dupTGC		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLX6	ENST00000518156.3	c.96_98dupGCA	p.Gln33dup	disruptive_inframe_insertion	1/3	1	NM_005222.4	ENSP00000428480.2

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 309 AN: 150048 Hom.: 2 Cov.: 29

Gnomad AFR AF: 0.00544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00199

Gnomad ASJ AF: 0.000870

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.0000993

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000594

Gnomad OTH AF: 0.00146

GnomAD3 exomes AF: 0.000849 AC: 161 AN: 189612 Hom.: 0 AF XY: 0.000785 AC XY: 81 AN XY: 103156

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000223

Gnomad EAS exome AF: 0.000591

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.000176

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.000893 AC: 1279 AN: 1431882 Hom.: 1 Cov.: 34 AF XY: 0.000887 AC XY: 630 AN XY: 710042

Gnomad4 AFR exome AF: 0.00422

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.000706

Gnomad4 SAS exome AF: 0.00142

Gnomad4 FIN exome AF: 0.000420

Gnomad4 NFE exome AF: 0.000779

Gnomad4 OTH exome AF: 0.000980

GnomAD4 genome AF: 0.00205 AC: 308 AN: 150144 Hom.: 2 Cov.: 29 AF XY: 0.00183 AC XY: 134 AN XY: 73326

Gnomad4 AFR AF: 0.00543

Gnomad4 AMR AF: 0.00199

Gnomad4 ASJ AF: 0.000870

Gnomad4 EAS AF: 0.000395

Gnomad4 SAS AF: 0.00126

Gnomad4 FIN AF: 0.0000993

Gnomad4 NFE AF: 0.000594

Gnomad4 OTH AF: 0.00145

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 07, 2023	This variant, c.96_98dup, results in the insertion of 1 amino acid(s) of the DLX6 protein (p.Gln44dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DLX6-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

DLX6-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 27, 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs530625473; hg19: chr7-96635363;